Heterocyclic compounds as P2X7 ion channel blockers

ABSTRACT

The present invention relates to a novel series of 4,5-diphenyl-2-amino-4,5-dihydro-imidazole derivatives of the formula II: 
                         
wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , X and Y are as defined herein. This invention also relates to methods of making these compounds. The compounds of this invention are P2X7 ion channel blockers and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases having an inflammatory component, including inflammatory bowel disease, rheumatoid arthritis and disease conditions associated with the central nervous system, such as stroke, Alzheimer&#39;s disease, etc.

This application is a division of U.S. application Ser. No. 10/896,166,filed Jul. 21, 2004, now allowed, which claims the benefit of U.S.Provisional Application No. 60/489,246, filed Jul. 21, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a series of dihydro-imidazole (alsoreferred to herein as imidazoline) compounds. More specifically, thepresent invention relates to a novel series of4,5-diphenyl-2-amino-4,5-dihydro-imidazole derivatives having certaingeometric configuration. This invention also relates to methods ofmaking these compounds. The compounds of this invention are P2X7 ionchannel blockers and are therefore useful as pharmaceutical agents,especially in the treatment and/or prevention of a variety of diseaseshaving an inflammatory component, including inflammatory bowel disease,rheumatoid arthritis and disease conditions associated with the centralnervous system, such as stroke, Alzheimer's disease, etc.

2. Description of the Art

The P2X7 receptor, a ligand-gated ion channel, is present on a varietyof cell types, mostly the ones believed to be involved in theinflammatory/immune process. In particular, macrophages, mast cells andlymphocytes (T and B) are known to have P2X7 receptor sites. Activationof the P2X7 receptor by extracellular nucleotides, particularly,adenosine triphosphate, leads to the release of interleukin-1β (IL-1β)and giant cell formation (macrophages/microglial cells), degranulation(mast cells) and L-selectin shedding (lymphocytes). P2X7 receptors arealso located on antigen presenting cells (APC), keratinocytes, salivaryacinar cells (parotid cells) and hepatocytes.

Thus, compounds exhibiting antagonistic activity at the P2X7 receptorsite are expected to show anti-inflammatory activity and thereby exhibittherapeutic efficacy in diseases due to P2X7 receptor activation. Thediseases that are implicated include rheumatoid arthritis, Alzheimer'sdisease, stroke and inflammatory bowel disease, psoriasis and variousother diseases where an inflammatory component is present. It has alsobeen reported that macrophages are also involved in the thermal injuriessuch as burns (see, e.g., Schwacha, Burns Vol. 29 pages 1-14 (2003)).

As noted above, the P2X7 protein is mainly localized to immune systemcells such as macrophages and microglia, see for example, Collo et al.,Neuropharmacology Vol. 36 pages 1277-1283 (1997). Also as noted above,activation of P2X7 results in the release of proinflammatory substancessuch as IL-1β and IL-18, see for example, Hlide et al., Journal ofNeurochemistry Vol. 75 pages 965-972 (2000); Perregaux et al., Journalof Immunology Vol. 165 pages 4615-4623 (2000). This is furtherdemonstrated by the fact that the mice lacking the P2X7 receptor areunable to release IL-1β via ATP stimulation. See Solle et al., Journalof Biological Chemistry Vol. 276 pages 125-132 (2001).

It has been reported that certain compounds act as P2X7 antagonists. Forexample, WO99/29660 and WO99/29661 disclose that certain adamantanederivatives exhibit P2X7 antagonistic activity having therapeuticefficacy in the treatment of rheumatoid arthritis and psoriasis.Similarly, WO99/29686 discloses that certain heterocyclic derivativesare P2X7 receptor antagonists and are useful as immunosuppressive agentsand treating rheumatoid arthritis, asthma, septic shock andatherosclerosis. Finally, WO00/71529 discloses certain substitutedphenyl compounds exhibiting immunosuppressing activity. All of thereferences described herein are incorporated herein by reference intheir entirety.

It is an object of this invention to provide a novel series ofcompounds, which can modify the activity of P2X7 receptor and thus therelease of the mediators of inflammation. It is further an object ofthis invention to provide a series of compounds that can treat oralleviate symptoms of inflammation caused due to the activation of P2X7receptor. A still further object of this invention is to providepharmaceutical compositions that are effective in the treatment orprevention of a variety of disease states, including the diseasesassociated with the central nervous system, such as stroke andAlzheimer's disease, inflammatory bowel disease, rheumatoid arthritis,and other diseases where an inflammatory component is present.

Other objects and further scope of the applicability of the presentinvention will become apparent from the detailed description to follow.

SUMMARY OF THE INVENTION

Thus in accordance with the practice of this invention there is provideda compound including enantiomers, stereoisomers, rotomers and tautomersof said compound and pharmaceutically acceptable salts, solvates orderivatives thereof. The compound of this invention has the generalstructure shown in formula II:

-   -   wherein:    -   R is hydrogen, C₁₋₆ alkyl, C₂₋₆ acyl, C₁₋₆ alkoxycarbonyl, or        -   C₆₋₁₂ aryloxycarbonyl;    -   R₁ and R₃ are the same or different and are each independently        selected from:        -   C₅₋₈ cycloalkyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydropyranyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl or naphthyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   aryl C₁₋₄ alkyl, C₅₋₈ cycloalkyl C₁₋₄ alkyl, heteroaryl C₁₋₄            alkyl, wherein aryl and heteroaryl are as defined above, and        -   wherein C₅₋₈ cycloalkyl, aryl or heteroaryl is optionally            substituted with one or more substituents selected from the            group consisting of halogen, C₁₋₄ alkyl, fluoroalkyl or            fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H,        -   —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; or    -   R₁ and R₃ taken together with the carbon atoms to which they are        attached form a cyclopentane, cyclohexane, cycloheptane or        cyclooctane;    -   R₂ and R₄ are the same or different and are each independently        selected from:        -   hydrogen, C₁₋₆ alkyl or fluoroalkyl of the formula            C_(n)H_(x)F_(y), wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1;    -   R₅ is hydrogen, C₃₋₈ cycloalkyl, C₂₋₄ alkynyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, pyridinonyl, tetrahydrofuranyl,            tetrahydropyranyl, dioxanyl, benzopyranyl,            dihydrobenzodioxanyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl, naphthyl or            anthracenyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   wherein C₅₋₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is            optionally substituted with one or more substituents            selected from the group consisting of halogen, C₁₋₄ alkyl,            fluoroalkyl fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H, —CO₂C₁₋₄ alkyl,            phenyl, phenoxy and benzyloxy;    -   X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, —(CH₂)_(a)—Z—(CH₂)_(b)—Z¹— or        —NHCO—,        -   wherein (CH₂) is optionally substituted with one or more            groups selected independently from:        -   hydroxy, C₁₋₆ alkoxy, arylaminocarbonyloxy, C₃₋₈ cycloalkyl,            C₁₋₆ alkyl or fluoroalkyl of the formula C_(n)H_(x)F_(y),            wherein n is an integer from 1 to 4, x is an integer from 0            to 8, y is an integer from 1 to 9 and sum of x and y is            2n+1, wherein said alkoxy or alkyl or fluoroalkyl is            optionally substituted with at least one substituent            selected from the group consisting of: hydroxy, —SH, C₁₋₄            alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   Z and Z¹ are the same or different and are each            independently selected from:        -   O, S, NR₆, NR₆—NR₆, —OCONH—, —NH—CO—NH—, —SO₂—NH—,            —(NR₆)SO₂— or        -   a bond,        -   wherein R₆ is selected from:        -   hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl or fluoroalkyl of the            formula C_(n)H_(x)F_(y), wherein n is an integer from 1 to            4, x is an integer from 0 to 8, y is an integer from 1 to 9            and sum of x and y is 2n+1, wherein said alkoxy or alkyl or            fluoroalkyl is optionally substituted with at least one            substituent selected from the group consisting of: hydroxy,            —SH, C₁₋₄ alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   a is an integer from 0 to 2 and b is an integer from 0 to 4            provided that sum of a and b is at least 1, and    -   with the proviso that:        -   when X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, where Z is S, R, R₂,            and R₄ are hydrogen, R₁ and R₃ are phenyl or p-Cl-phenyl, a            is 0 and b is 1, R₅ is not hydrogen or phenyl; and        -   when X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, where Z is a bond, R,            R₂, and R₄ are hydrogen, R₁ and R₃ are phenyl, a is 0 and b            is 1, R₅ is not hydrogen.

In another aspect of this invention there is also provided a method forthe treatment of diseases selected from the group consisting ofinflammatory bowel disease, rheumatoid arthritis, and diseasesassociated with central nervous system, which comprises administering toa patient in need of such treatment a therapeutically effective amountof a compound of the formula (II), as described herein, including thepharmaceutically acceptable salt thereof, optionally in combination witha pharmaceutically acceptable carrier. However, in this aspect of theinvention all of the compounds encompassing the generic scope of theformula (II) are useful in the method of this invention.

In yet another aspect of this invention there is also provided apharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt thereof in combination with at least onepharmaceutically acceptable carrier for treating diseases selected fromthe group consisting of inflammatory bowel disease, rheumatoidarthritis, and diseases associated with central nervous system, whereinsaid compound is of the formula (II) as described herein, including thepharmaceutically acceptable salt thereof, optionally in combination witha pharmaceutically acceptable carrier. Again, in this aspect of theinvention all of the compounds encompassing the generic scope of theformula (II) are used in the composition of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The terms as used herein have the following meanings:

As used herein, the expression “C₁₋₆ alkyl” includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyland tert-butyl. Derived expressions such as “C₁₋₄alkoxy”,“C₁₋₄alkoxyC₁₋₄alkyl”, “hydroxyC₁₋₄alkyl”, “C₁₋₄alkylcarbonyl”,“C₁₋₄alkoxycarbonylC₁₋₄alkyl”, “C₁₋₄alkoxycarbonyl”, “aminoC₁₋₄alkyl”,“C₁₋₄alkylamino”, “C₁₋₄alkylcarbamoylC₁₋₆alkyl”,“C₁₋₄dialkylcarbamoylC₁₋₄alkyl” “mono- or di-C₁₋₄alkylaminoC₁₋₄alkyl”,“aminoC₁₋₄alkylcarbonyl” “diphenylC₁₋₄alkyl”, “phenylC₁₋₄alkyl”,“phenylcarboylC₁₋₄alkyl” and “phenoxyC₁₋₄alkyl” are to be construedaccordingly.

As used herein, the expression “C₂₋₆alkenyl” includes ethenyl andstraight-chained or branched propenyl, butenyl, pentenyl and hexenylgroups. Similarly, the expression “C₂₋₆alkynyl” includes ethynyl andpropynyl, and straight-chained or branched butynyl, pentynyl and hexynylgroups.

As used herein, the expression “C₁₋₆ perfluoroalkyl” means that all ofthe hydrogen atoms in said alkyl group are replaced with fluorine atoms.Illustrative examples include trifluoromethyl and pentafluoroethyl, andstraight-chained or branched heptafluoropropyl, nonafluorobutyl,undecafluoropentyl and tridecafluorohexyl groups. Derived expression,“C₁₋₆ perfluoroalkoxy”, is to be construed accordingly.

As used herein, the expression “C₃₋₈cycloalkyl” means cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, the expression “C₃₋₈cycloalkylC₁₋₆alkyl” means that theC₃₋₈cycloalkyl as defined herein is further attached to C₁₋₆alkyl asdefined herein. Representative examples include cyclopropylmethyl,1-cyclobutylethyl, 2-cyclopentylpropyl, cyclohexylmethyl,2-cycloheptylethyl and 2-cyclooctylbutyl and the like.

“Halogen” or “halo” means chloro, fluoro, bromo, and iodo.

As used herein, “patient” means a warm blooded animal, such as forexample rat, mice, dogs, cats, guinea pigs, and primates such as humans.

As used herein, the expression “pharmaceutically acceptable carrier”means a non-toxic solvent, dispersant, excipient, adjuvant, or othermaterial which is mixed with the compound of the present invention inorder to permit the formation of a pharmaceutical composition, i.e., adosage form capable of administration to the patient. One example ofsuch a carrier is pharmaceutically acceptable oil typically used forparenteral administration.

The term “pharmaceutically acceptable salts” as used herein means thatthe salts of the compounds of the present invention can be used inmedicinal preparations. Other salts may, however, be useful in thepreparation of the compounds according to the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, hydrobromic acid, sulfuricacid, methanesulfonic acid, 2-hydroxyethanesulfonic acid,p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid,malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid,salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoicacid, phenylacetic acid, benzoic acid, oxalic acid, citric acid,tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid,carbonic acid or phosphoric acid. The acid metal salts such as sodiummonohydrogen orthophosphate and potassium hydrogen sulfate can also beformed. Also, the salts so formed may present either as mono- or di-acidsalts and can exist either as hydrated or can be substantiallyanhydrous. Furthermore, where the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g. quaternary ammonium salts.

The expression “stereoisomers” is a general term used for all isomers ofthe individual molecules that differ only in the orientation of theiratoms in space. Typically it includes mirror image isomers that areusually formed due to at least one asymmetric center, (enantiomers).Where the compounds according to the invention possess two or moreasymmetric centers, they may additionally exist as diastereoisomers,also certain individual molecules may exist as geometric isomers(cis/trans). It is to be understood that all such isomers and mixturesthereof in any proportion are encompassed within the scope of thepresent invention.

In a broad sense, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a few of the specificembodiments as disclosed herein, the term “substituted” meanssubstituted with one or more substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, hydroxy, —CO₂H,an ester, an amide, C₁-C₆ alkoxy, C₁-C₆ perfluoroalkoxy, —NH₂, Cl, Br,I, F, —NH-lower alkyl, and —N(lower alkyl)₂. However, any of the othersuitable substituents known to one skilled in the art can also be usedin these embodiments.

“Therapeutically effective amount” means an amount of the compound whichis effective in treating the named disorder or condition.

In one aspect of this invention, there is disclosed a series ofimidazoline compounds (also referred to herein as dihydro imidazolecompounds) having certain therapeutic properties. In this aspect of theinvention, the imidazoline compound includes all of the possibleenantiomers, stereoisomers, rotomers and tautomers. The pharmaceuticallyacceptable salts, solvates or derivatives thereof are also included inthis aspect of the invention. The imidazoline compound of this inventionis having the general structure shown in formula I:

-   -   wherein:    -   R is hydrogen, C₁₋₆ alkyl, C₂₋₆ acyl, C₁₋₆ alkoxycarbonyl, or        -   C₆₋₁₂ aryloxycarbonyl;    -   R₁ and R₃ are the same or different and are each independently        selected from:        -   C₅₋₈ cycloalkyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydropyranyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl or naphthyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   aryl C₁₋₄ alkyl, C₅₋₈ cycloalkyl C₁₋₄ alkyl, heteroaryl C₁₋₄            alkyl, wherein aryl and heteroaryl are as defined above, and        -   wherein C₅₋₈ cycloalkyl, aryl or heteroaryl is optionally            substituted with one or more substituents selected from the            group consisting of halogen, C₁₋₄ alkyl, fluoroalkyl or            fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H,        -   —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; or    -   R₁ and R₃ taken together with the carbon atoms to which they are        attached form a cyclopentane, cyclohexane, cycloheptane or        cyclooctane;    -   R₂ and R₄ are the same or different and are each independently        selected from:        -   hydrogen, C₁₋₆ alkyl or fluoroalkyl of the formula            C_(n)H_(x)F_(y), wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1;    -   R₅ is hydrogen, C₃₋₈ cycloalkyl, C₂₋₄ alkynyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, pyridinonyl, tetrahydrofuranyl,            tetrahydropyranyl, dioxanyl, benzopyranyl,            dihydrobenzodioxanyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl, naphthyl or            anthracenyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   wherein C₅₋₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is            optionally substituted with one or more substituents            selected from the group consisting of halogen, C₁₋₄ alkyl,            fluoroalkyl fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H, —CO₂C₁₋₄ alkyl,            phenyl, phenoxy and benzyloxy;    -   X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, —(CH₂)_(a)—Z—(CH₂)_(b)—Z¹— or        —NHCO—,        -   wherein (CH₂) is optionally substituted with one or more            groups selected independently from:        -   hydroxy, C₁₋₆ alkoxy, arylaminocarbonyloxy, C₃₋₈ cycloalkyl,            C₁₋₆ alkyl or fluoroalkyl of the formula C_(n)H_(x)F_(y),            wherein n is an integer from 1 to 4, x is an integer from 0            to 8, y is an integer from 1 to 9 and sum of x and y is            2n+1, wherein said alkoxy or alkyl or fluoroalkyl is            optionally substituted with at least one substituent            selected from the group consisting of: hydroxy, —SH, C₁₋₄            alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   Z and Z¹ are the same or different and are each            independently selected from:        -   O, S, NR₆, NR₆—NR₆, —OCONH—, —NH—CO—NH—, —SO₂—NH—,            —(NR₆)SO₂— or        -   a bond,        -   wherein R₆ is selected from:        -   hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl or fluoroalkyl of the            formula C_(n)H_(x)F_(y), wherein n is an integer from 1 to            4, x is an integer from 0 to 8, y is an integer from 1 to 9            and sum of x and y is 2n+1, wherein said alkoxy or alkyl or            fluoroalkyl is optionally substituted with at least one            substituent selected from the group consisting of: hydroxy,            —SH, C₁₋₄ alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   a is an integer from 0 to 2 and b is an integer from 0 to 4            provided that sum of a and b is at least 1, and    -   with the proviso that:        -   when X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, where Z is S, R, R₂,            and R₄ are hydrogen, R₁ and R₃ are phenyl or p-Cl-phenyl, a            is 0 and b is 1, R₅ is not hydrogen or phenyl; and        -   when X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, where Z is a bond, R,            R₂, and R₄ are hydrogen, R₁ and R₃ are phenyl, a is 0 and b            is 1, R₅ is not hydrogen.

In a preferred embodiment of this invention, there is disclosed acompound including enantiomers, stereoisomers, rotomers and tautomers ofsaid compound and pharmaceutically acceptable salts, solvates orderivatives thereof. The compound of this embodiment is having thegeneral structure shown in formula II:

-   -   wherein:    -   R is hydrogen, C₁₋₆ alkyl, C₂₋₆ acyl, C₁₋₆ alkoxycarbonyl, or        -   C₆₋₁₂ aryloxycarbonyl;    -   R₁ and R₃ are the same or different and are each independently        selected from:        -   C₅₋₈ cycloalkyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydropyranyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl or naphthyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   aryl C₁₋₄ alkyl, C₅₋₈ cycloalkyl C₁₋₄ alkyl, heteroaryl C₁₋₄            alkyl, wherein aryl and heteroaryl are as defined above, and        -   wherein C₅₋₈ cycloalkyl, aryl or heteroaryl is optionally            substituted with one or more substituents selected from the            group consisting of halogen, C₁₋₄ alkyl, fluoroalkyl or            fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H,        -   —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; or    -   R₁ and R₃ taken together with the carbon atoms to which they are        attached form a cyclopentane, cyclohexane, cycloheptane or        cyclooctane;    -   R₂ and R₄ are the same or different and are each independently        selected from:        -   hydrogen, C₁₋₆ alkyl or fluoroalkyl of the formula            C_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is an            integer from 0 to 8, y is an integer from 1 to 9 and sum of            x and y is 2n+1;    -   R₅ is hydrogen, C₃₋₈ cycloalkyl, C₂₋₄ alkynyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, pyridinonyl, tetrahydrofuranyl,            tetrahydropyranyl, dioxanyl, benzopyranyl,            dihydrobenzodioxanyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl, naphthyl or            anthracenyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzoxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   wherein C₅₋₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is            optionally substituted with one or more substituents            selected from the group consisting of halogen, C₁₋₄ alkyl,            fluoroalkyl fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H, —CO₂C₁₋₄ alkyl,            phenyl, phenoxy and benzyloxy;    -   X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, —(CH₂)_(a)—Z—(CH₂)_(b)—Z¹— or        —NHCO—,        -   wherein (CH₂) is optionally substituted with one or more            groups selected independently from:        -   hydroxy, C₁₋₆ alkoxy, arylaminocarbonyloxy, C₃₋₈ cycloalkyl,            C₁₋₆ alkyl or fluoroalkyl of the formula C_(n)H_(x)F_(y),            wherein n is an integer from 1 to 4, x is an integer from 0            to 8, y is an integer from 1 to 9 and sum of x and y is            2n+1, wherein said alkoxy or alkyl or fluoroalkyl is            optionally substituted with at least one substituent            selected from the group consisting of: hydroxy, —SH, C₁₋₄            alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   Z and Z¹ are the same or different and are each            independently selected from:        -   O, S, NR₆, NR₆—NR₆, —OCONH—, —NH—CO—NH—, —SO₂—NH—,            —(NR₆)SO₂— or        -   a bond,        -   wherein R₆ is selected from:        -   hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl or fluoroalkyl of the            formula C_(n)H_(x)F_(y), wherein n is an integer from 1 to            4, x is an integer from 0 to 8, y is an integer from 1 to 9            and sum of x and y is 2n+1, wherein said alkoxy or alkyl or            fluoroalkyl is optionally substituted with at least one            substituent selected from the group consisting of: hydroxy,            —SH, C₁₋₄ alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   a is an integer from 0 to 2 and b is an integer from 0 to 4            provided that sum of a and b is at least 1, and    -   with the proviso that:        -   when X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, where Z is S, R, R₂ and            R₄ are hydrogen, R₁ and R₃ are phenyl or p-Cl-phenyl, a is 0            and b is 1, R₅ is not hydrogen or phenyl; and        -   when X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, where Z is a bond, R,            R₂, and R₄ are hydrogen, R₁ and R₃ are phenyl, a is 0 and b            is 1, R₅ is not hydrogen.

In one embodiment of this invention the compound of formula (II) havingX—Y as —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is NR₆, wherein R₆ is hydrogenor methyl, and a is 0 or 1 and b is 1 is preferred. In this embodimentof the invention the compound of formula (II) further having R₁ and R₃as phenyl, R₄ as hydrogen and R₂ as hydrogen or methyl is particularlypreferred. Thus, the compound in accordance with this preferredembodiment may generically be represented by the formula (III):

In formula (III), as noted herein R₂ and R₆ are hydrogen or methyl, a is0 or 1, R and R₅ are as defined above. Specific compounds in accordancewith this embodiment of the invention are listed below:

-   [(cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]benzylamine,-   cis-4,5-diphenyl-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4,5-trifluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,6-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(3,4-difluorobenzyl)amino]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,5-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chloro-3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chloro-4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-chloro-2-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chlorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-chlorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-chlorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,4-dichlorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4-dichlorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-bromobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-bromobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-trifluoromethylbenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-trifluoromethylbenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-methoxybenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methoxybenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-methoxybenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4,5-trimethoxybenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-methylbenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methylbenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-methylbenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(cyclohexylmethyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(N-benzyl,    N-methyl)amino-4,5-dihydro-1H-imidazole, and-   2-(4-fluorobenzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic    acid phenyl ester

In an additional feature of the above mentioned embodiment, the phenylmoieties on the cis-4,5-diphenyl-imidazoline compounds of formula (III)are substituted each with 1 to 3 halogens and R group is hydrogen. Inthis embodiment the suitable halogens are fluorine, chlorine or bromine.Thus, in accordance with this aspect of the embodiment of this inventionthe compound is generically represented by formula (IV):

As noted above, in formula (IV), R_(a) is halogen, R₂ and R₆ arehydrogen or methyl and a is 0 or 1, and R₅ is as defined above. Specificcompounds encompassing this embodiment of this invention are enumeratedbelow:

-   cis-4,5-bis(2-fluorophenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-fluorophenyl)-2-(3-methylbenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-fluorophenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-fluorophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-4-methyl-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-4-methyl-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-fluorophenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-fluorophenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-fluorophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-fluorophenyl)-4-methyl-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-fluorophenyl)-4-methyl-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-chlorophenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-chlorophenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-chlorophenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-chlorophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-chlorophenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-chlorophenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-chlorophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-chlorophenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-chlorophenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-chlorophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-bromophenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-bromophenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,    and-   cis-4,5-bis(2-bromophenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole.

In yet an additional feature of the above mentioned embodiment of thisinvention the phenyl moieties on the cis-4,5-diphenyl-imidazolinecompounds of formula (III) are substituted each with 1 to 3 C₁₋₄ alkyl,and R is hydrogen. In this embodiment, the preferred C₁₋₄ alkyl ismethyl. Thus, in accordance with this embodiment of this invention thespecific compounds are as listed below:

-   cis-4,5-bis(2-methylphenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-methylphenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-methylphenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(2-methylphenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-methylphenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-methylphenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-methylphenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-methylphenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-methylphenyl)-2-benzylamino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-methylphenyl)-2-(3-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-methylphenyl)-2-(4-fluorobenzyl)amino-4,5-dihydro-1H-imidazole,    and-   cis-4,5-bis(4-methylphenyl)-2-(3,4-difluorobenzyl)amino-4,5-dihydro-1H-imidazole.

In another embodiment of this invention, the compound in which R₁ and R₃taken together with the carbon atoms to which they are attached form acyclohexane ring. In this embodiment R, R₂ and R₄ are hydrogen. Thus, inaccordance with this aspect of the embodiment of this invention thecompound is generically represented by formula (V):

As noted above, in formula (V), R₆ is hydrogen or methyl and a is 0 or1, and R₅ is as defined above. Specific compounds encompassing thisembodiment of this invention are enumerated below:

-   (cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-benzylamine,-   (cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(3-fluorobenzyl)amine,-   (cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(4-fluorobenzyl)amine,    and-   (cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(3,4-difluorobenzyl)amine.

In another embodiment of this invention the compound of formula (II)having X—Y as —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is NR₆, wherein R₆ ishydrogen, and a is 0 and b is 2 is preferred. In this embodiment of theinvention the compound of formula (II) further having R₁ and R₃ asphenyl, R, R₂ and R₄ as hydrogen is particularly preferred. Thus, thecompound in accordance with this embodiment may generically berepresented by the formula (VI):

In formula (VI), R₅ is as defined above. Specific compounds inaccordance with this embodiment of this invention are listed below:

-   cis-4,5-diphenyl-2-[(2-phenyl)ethyl]amino-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[2-(2-fluorophenyl)ethyl]amino-4,5-dihydro-1H-imidazole,    and-   cis-4,5-diphenyl-2-[2-(4-fluorophenyl)ethylamino]-4,5-dihydro-1H-imidazole.

In yet another embodiment of this invention, the compound of formula(II) having X—Y as —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is a bond, and ais 0 and b is 2 to 4 is preferred. In this embodiment, the methylenegroup, CH₂, is optionally substituted with hydroxy, methyl or phenyl.Additionally, in this embodiment of the invention, the compound offormula (II) further having R₁ and R₃ as phenyl or pyridyl, whereinphenyl is optionally substituted with fluorine, and R and R₄ as hydrogenand R₂ as hydrogen or methyl is particularly preferred. Thus, thecompound in accordance with this embodiment may generically berepresented by the formula (VII):

In formula (VII), as noted above, R_(b) is either hydrogen, hydroxy,methyl or phenyl, R₁ and R₃ are independently phenyl, pyridyl or phenylsubstituted with fluorine, R₂ is hydrogen or methyl, and R₅ is asdefined above. Specific compounds in accordance with this embodiment ofthis invention are listed below:

-   cis-4,5-diphenyl-2-(2-phenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(2-fluorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(3-fluorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(4-fluorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(2-chlorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(3-chlorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(4-chlorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(3,4-dichlorophenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(2-phenylethyl)-4,5-dihydro-1H-imidazole,-   2-(cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1-phenylethan-1-ol,-   cis-4,5-diphenyl-2-(2-(2-methoxyphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(4-methoxyphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(3,4-dimethoxyphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(2-methylphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(3-methylphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(4-methylphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-((2S)-phenyl)propyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(3,5-difluorophenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-(4-trifluoromethylphenyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[2-(2-pyridyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[2-(2-pyridyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[2-(3-pyridyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[2-(4-tetrahydropyranyl)ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(2-fluorophenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(3-fluorophenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(4-fluorophenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(3,4-difluorophenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(2-chlorophenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(3,4-dichlorophenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(2-phenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(2-methylphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(3-methylphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(4-methylphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(4-trifluoromethylphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(3,4-ditrifluoromethylphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(2-methoxyphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(4-methoxyphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[2-(3,4-dimethoxyphenyl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-4-methyl-2-(2-phenylethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-[(2-thiophen-2-yl)ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(4-fluorophenyl)-2-(2-phenylethyl)-4,5-dihydro-1H-imidazole,-   2-phenethyl-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole,-   2-[2-methyl-(2S)-phenyl)-propyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole    trifluoroacetate,-   2-[2,2-diphenylethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole    trifluoroacetate,-   2-[1-methyl-2-phenylethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole    trifluoroacetate,-   2-[3-phenyl-propyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole    trifluoroacetate, and-   2-[4-phenyl-butyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole    trifluoroacetate.

In yet an additional embodiment of this invention, the compound offormula (II) having X—Y as —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is a bond,and a is 0 and b is 1 is preferred. In this embodiment, the methylenegroup, CH₂, is optionally substituted with hydroxy, methoxy, methyl orphenylaminocarbonyloxy. Furthermore, the (CH₂) may optionally besubstituted with at least two carbon atoms all of which taken togetherform a cyclic ring. For instance, when CH₂ is substituted with twocarbon atoms all of which together form a cyclopropyl ring. Similarly,when the CH₂ group is substituted with three carbon atoms all of whichtogether can form a cyclobutyl ring, and so on. The cyclopropyl group isparticularly preferred.

Additionally, in this embodiment of the invention, the compound offormula (II) further having R₁ and R₃ as phenyl or pyridyl, whereinphenyl is optionally substituted with fluorine, and R and R₄ as hydrogenand R₂ as either hydrogen or methyl is particularly preferred. Thus, thecompound in accordance with this embodiment may generically berepresented by the formula (VIII):

In formula (VIII), as noted above, R_(c) is either hydrogen, hydroxy,methoxy methyl or phenylaminocarbonyloxy, R₁ and R₃ are independentlyphenyl, pyridyl or phenyl substituted with fluorine, R₂ is hydrogen ormethyl, and R₅ is as defined above. In addition, as also noted above,when R_(c) is a carbon chain of two or more carbon atoms, it can form acyclic ring with the carbon atom to which it is attached. Thus, whenR_(c) is a two carbon chain it can form a cyclopropyl ring with thecarbon to which it is attached. A generic structure of this type may berepresented by the formula VIIIA:

Specific compounds in accordance with this embodiment of the inventionare listed below:

-   cis-4,5-diphenyl-2-(2-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-fluoro-4-methylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-methyl-5-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(4-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,3-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,4-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,5-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,6-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,6-difluoro-3-methylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(2,4-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(3,4-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chlorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-chlorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-chlorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(3-chlorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-fluoro-3-chlorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chloro-4-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chloro-6-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-chloro-4-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-(4-chlorophenyl)-1-ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-{(4-chlorophenyl)-1-methyl}ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-(4-chlorophenyl)-1-cyclopropyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-(2,4-dichlorophenyl)-1-cyclopropyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-bromobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-trifluoromethylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-methylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-methylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,5-dimethylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,4,6-trimethylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,3-dimethoxybenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,5-dimethoxybenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-methanesulfonylbenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(1-phenyl)-(1S)-ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(1-phenyl)-(1R)-ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-(4-isobutylphenyl)-1-ethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(1-(4-chlorophenyl)-1-ethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-phenyl-1-cyclopropyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-naphthalen-2-yl)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(methoxy-phenyl-methyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[1-(2-fluorobiphenyl-4-yl)-1-ethyl]-4,5-dihydro-1H-imidazole,-   cis-(4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanol,-   phenyl-carbamic acid    cis-(4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methyl ester,-   1-[(cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-pyridin-2-one,-   cis-4,5-bis-(3-fluorophenyl)-2-(3-chlorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis-(3-fluorophenyl)-2-(3,4-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis-(3-fluorophenyl)-2-(2,4-difluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis-(3-fluorophenyl)-2-(2-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis-(3-fluorophenyl)-2-(4-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-bis-(3-fluorophenyl)-4-methyl-2-(4-fluorobenzyl)-4,5-dihydro-1H-imidazole,-   2-methyl-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole, and-   2-indan-2-ylmethyl-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole    trifluoroacetate.

In yet another embodiment of this invention, the compound of formula(II) having X—Y as —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is S, and a and bare 0 or 1 is preferred. Additionally, in this embodiment of theinvention, the compound of formula (II) further having R₁ and R₃ asphenyl or pyridyl, and R and R₄ as hydrogen and R₂ as hydrogen or methylis particularly preferred. Thus, the compound in accordance with thisembodiment may generically be represented by the formula (IX):

In formula (IX), as noted above, R₁ and R₃ are independently phenyl orpyridyl, R₂ is hydrogen or methyl, a and b are 0 or 1, and R₅ is asdefined above. Specific compounds encompassed by this aspect of theembodiment may be enumerated as follows:

-   cis-4,5-diphenyl-2-[(phenylsulfanyl)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(benzylsulfanyl)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(benzylsulfanyl)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-benzylthio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-fluorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-fluorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-fluorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4-difluorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chloro-4-fluorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chloro-6-fluorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-chlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-chlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-chlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,4-dichlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,5-dichlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4-dichlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,6-dichlorobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-bromobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-bromobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-bromobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-iodobenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-methylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-methylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,4-dimethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,5-dimethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,3,5,6-tetramethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2,3,4,5,6-pentamethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-isopropylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-tert-butylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-trifluoromethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-trifluoromethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-trifluoromethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,5-ditrifluoromethylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-trifluoromethoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-trifluoromethoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-methoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,5-dimethoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4,5-trimethoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-phenoxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-benzyloxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3,4-dibenzyloxybenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-phenylbenzyl)thio-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(naphthalen-1-yl)methylthio]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(2-methylnaphthalen-1-yl)methylthio]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(anthracen-9-yl)methylthio]-4,5-dihydro-1H-imidazole,-   4-[(cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)thiomethyl]benzoic    acid ethyl ester, and-   2-phenylthiomethyl-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole.

Still in another embodiment of this invention, the compound of formula(II) having X—Y as —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is O, and a and bare 0, 1 or 2 is preferred. Furthermore, in this embodiment the (CH₂) isoptionally substituted with methyl, n-propyl or cyclopropyl.Additionally, in this embodiment of the invention, the compound offormula (II) further having R₁ and R₃ as phenyl or phenyl substitutedwith fluorine or methoxy, and R, R₂, R₄ as hydrogen or methyl isparticularly preferred. Thus, the compound in accordance with thisembodiment may generically be represented by the formula (X):

In formula (X), as noted above, R₁ and R₃ are independently phenyl orphenyl substituted with fluorine or methoxy, R, R₂, R₄ as hydrogen ormethyl, a and b are 0, 1 or 2, and R₅ is as defined above. In addition,one or more of the (CH₂) group may optionally be substituted withmethyl, n-propyl or cyclopropyl. Specific compounds encompassed by thisaspect of the embodiment may be enumerated as follows:

-   cis-4,5-diphenyl-2-[(2-phenethyloxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-benzyloxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-fluorobenzyloxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methylbenzyloxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-methoxybenzyloxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-trifluoromethylbenzyloxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-phenoxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-phenoxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4,5-dimethyl-2-phenoxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(1-phenoxyethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(2-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(3-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-(3-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-(4-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(2-chlorophenoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-methoxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-methoxymethyl-4-methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-isopropoxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-isopropoxymethyl-4-methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(1-ethynyl-1-butoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[[(cyclopropyl)methoxy]methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(dicyclopropylmethoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(1-cyclopropyl-1-ethoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(cyclobutoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-cyclopentyloxymethyl-4-methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(cyclopentylmethoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(1-cyclopentyl-1-ethoxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-cyclohexyloxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-cyclohexyloxymethyl-4-methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-cycloheptyloxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-cyclooctyloxymethyl-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[[(tetrahydrofuran-2-yl)methoxy]methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-2-[(tetrahydropyran-4-yloxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(tetrahydropyran-4-yloxy)methyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(1,3-dioxan-5-yl)oxymethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(1-benzopyran-4-yloxy)methyl]-4,5-dihydro-1H-imidazoline,-   cis-4,5-diphenyl-2-(cyclohexylmethoxymethyl)-4,5-dihydro-1H-imidazole,-   cis-4,5-diphenyl-4-methyl-2-[(2,3-dihydrobenzo-1,4-dioxan-2-yl)methoxymethyl]-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(2-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(3-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-1,4-dimethyl-2-(3-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-1,5-dimethyl-2-(3-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,-   cis-4,5-bis(3-fluorophenyl)-2-(4-fluorophenoxy)methyl-4,5-dihydro-1H-imidazole,    and-   cis-(5-methoxyphenyl-4-phenyl)-2-[[(cyclopentyl)methoxy]methyl]-4,5-dihydro-1H-imidazole.

Finally, in the above embodiment the compound of formula X having R₁ andR₃ as phenyl, methyl or pyridyl, R as hydrogen, and R₂ and R₄ ashydrogen or methyl is also preferred. Specific compounds encompassingthis preferred embodiment are listed below:

-   2-(phenoxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazole,-   2-(3-fluorophenoxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazole,-   2-(benzyloxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazole,-   2-(3-fluorobenzyloxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazole,-   2-phenoxymethyl-(cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole,-   2-[(3-fluorophenoxy)methyl]-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole,    and-   2-cyclohexyloxymethyl-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole.

In another aspect of this invention there is also disclosed a compoundincluding enantiomers, stereoisomers, rotomers and tautomers of saidcompound and pharmaceutically acceptable salts, solvates or derivativesthereof, with said compound having the general structure shown informula XI:

-   -   wherein:    -   R is hydrogen, C₁₋₆ alkyl, C₂₋₆ acyl, C₁₋₆ alkoxycarbonyl, or        -   C₆₋₁₂ aryloxycarbonyl;    -   R₁ and R₃ are the same or different and are each independently        selected from:        -   C₅₋₈ cycloalkyl,        -   heterocycle, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydropyranyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl or naphthyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   aryl C₁₋₄ alkyl, C₅₋₈ cycloalkyl C₁₋₄ alkyl, heteroaryl C₁₋₄            alkyl, wherein aryl and heteroaryl are as defined above, and        -   wherein C₅₋₈ cycloalkyl, aryl or heteroaryl is optionally            substituted with one or more substituents selected from the            group consisting of halogen, C₁₋₄ alkyl, fluoroalkyl or            fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H,        -   —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; or    -   R₁ and R₃ taken together with the carbon atoms to which they are        attached form a cyclopentane, cyclohexane, cycloheptane or        cyclooctane; and    -   R₂ and R₄ are the same or different and are each independently        selected from:        -   hydrogen, C₁₋₆ alkyl or fluoroalkyl of the formula            C_(n)H_(x)F_(y), wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1;    -   A and D are the same or different and are each independently        CH₂, NH, O or S;    -   B is CH or N; and    -   E, F, G and H are the same or different and are each        independently CH or N.

In a preferred aspect of this invention, the compound of this aspect ofthe invention preferably feature the following substituents:

-   -   R is hydrogen;    -   R₁ and R₃ are both phenyl;    -   R₂ and R₄ are the same or different and are each independently        hydrogen or methyl;    -   A and D are the same or different and are each independently CH₂        or NH;    -   B is CH; and    -   E, F, G and H are CH.

As an illustrative compound of this aspect of the invention thefollowing can specifically be enumerated:

-   2-indan-2-yl-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate.

The compounds of this invention can be synthesized by any of theprocedures known to one skilled in the art. Specifically, several of thestarting materials used in the preparation of the compounds of thisinvention are known or are themselves commercially available. Thecompounds of this invention and several of the precursor compounds mayalso be prepared by methods used to prepare similar compounds asreported in the literature. See for example, Sharaf, M. A., et al., J.Chem. Research (S), 1996, 322-323, which discloses preparative methodsfor a few of the precursor compounds. A few of the2-thiosubstituted-4,5-dihydro-1H-imidazoles are also disclosed in U.S.Pat. Nos. 4,379,159; and 4,308,277. A few other imidazoline derivativesare also disclosed in German Patent Nos. DE 27 01 372; and DE 28 54 428;and EP Patent No. 0 000 208. Each of these references is hereinincorporated by reference in its entirety.

Further, a few of the 2-benzylthio-4,5-dihydro-1H-imidazoles have beenreported; see, for example, Sharaf, M. A. et al., Phosphorus, Sulfur,and Silicon, 1994, 92, 19-27; and Hammouda, H. A., et al., Gazz. Chim.Ital., 1984, 114, 201-204. Similarly, a few derivatives of2-benzylamino-4,5-dihydro-1H-imidazoles have also been reported; see,for example, Isobe, T., et al., Chem. Commun., 2001, 243-244; and IsobeT., et al., J. Org. Chem., 2000, 65, 7774-7778.

More specifically, the compounds disclosed herein can be synthesizedaccording to the following procedures of Schemes 1-11, wherein the X, Y,Z, R₁, R₂, R₃ and R_(a) substituents are as defined for Formula (II) oras defined for Formulae (III) to (X) above unless otherwise indicated.

In general, the compounds of this invention, the imidazolinederivatives, can be synthesized from the starting 1,2-diaminoethanederivative, which is prepared following the procedures shown inScheme 1. Thus, Scheme 1 illustrates a synthesis of a class of1,2-diphenyl-diaminoethane derivatives, 3, in which both R₁ and R₃ arethe same, i.e., the substituted or unsubstituted phenyl group. Thesubstituents R₂ and R₄ are hydrogen in this case. In accordance withthis procedure, a suitable substituted benzaldehyde, 1 is reacted withammonium acetate under suitable reaction conditions to form theintermediate 2, which is further reacted with sulfuric acid to formcis-1,2-diaminoethane derivative, 3, the starting material for thesynthesis of a variety of 4,5-diphenyl-midazoline compounds of thisinvention. The coupling reaction as described herein can be effected byany of the methods known in the art. In general, this step is carriedout at an elevated temperature typically in the range of from about 80°C. to 150° C. for a sufficient length of time to drive the reaction tocompletion. Typically, the reaction is carried out for a period of about8 to 16 hours or longer depending upon the reaction temperature.

The crude, coupling product, 2 is then contacted with a suitable acidsuch as sulfuric acid at elevated temperature to form the diaminocompound, 3. The reaction can again be carried out by any of theprocedures known in the art. Typically, the reaction is effected atelevated temperatures in the range of from about 80° C. to 150° C.Various other diamino compounds, 3 in which R₁ and R₃ groups are thesame can be synthesized using the procedures of Scheme 1 and employingthe desirable aldehyde.

Alternatively, the starting 1,2-diamino compound can also be synthesizedfollowing the steps as set forth in Scheme 2. In accordance with thisprocedure, a much broader class of diamino compounds, 8 can be prepared.

In Scheme 2, step 1, the 1,2-diketo compound, 4 is first contacted withsulfamide to form the thiadiazole-1,1-dioxide, 5. This reaction isgenerally carried out in the presence of an acid such as hydrogenchloride and in the presence of any art recognized solvent such asmethanol. The reaction can generally be carried out at ambientconditions.

The thiadiazole-1,1-dioxide, 5 can then be substituted with suitablesubstituents to form the substituted derivative, 6. Generally, themethod depicted in Scheme 2 is suitable for the preparation ofmonosubstituted derivative, 6. Thus, for example, the intermediate, 5can be contacted with suitable Grignard reagent, such as R₂MgBr to formthe alkylated derivative, 6 (i.e., wherein R₂ is a suitable alkyl oraryl group and R₄ is hydrogen). The substitution reaction using aGrignard agent is carried out using conditions well known in the artsuch as in an ethereal solvent at a temperature of around −10° C. to 20°C. In an analogous manner, the Grignard product can further be treatedwith another Grignard reagent such as R₄MgBr to form the disubstituteddiamine, which can be used to prepare various other disubstitutedimidazoline compounds of this invention (i.e., wherein R₄ is as definedherein).

In Scheme 2, step 3, the substituted derivative, 6 is subjected toreductive conditions to form the product 7. For instance, 6 is treatedwith sodium borohydride in an art recognized solvent such as methanol toform the product 7, which can be cleaved under acidic reactionconditions to form the diamine, 8.

Scheme 2A illustrates a variation of Scheme 2 in which preparation ofthe tetrasubstituted-1,2-diamine is shown. Thus, thethiadiazole-1,1-dioxide, 5 is contacted with two molar equivalents ofGrignard reagent to form the tetrasubstituted-thiadiazole-1,1-dioxide,7A, which is further cleaved under acidic reaction conditions to formthe tetrasubstiuted-1,2-diamine, 8A in which R₄ is same as R₂.

Alternatively, as stated above, the 1,2-diamine having different R₂ andR₄ groups can also by prepared in an analogous manner following theprocedures set forth in Scheme 2 or Scheme 2A by contacting theintermediate, 5 with two different Grignard reagents in two separatesequential steps as shown in Scheme 2B.

Scheme 3 illustrates general procedures that can be used to prepare aclass of imidazoline compounds of this invention in which X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)— and wherein Z is NR₆ and a is 0. An analogousprocedure can be employed for the preparation of various other compoundsof this invention with suitable modifications known in the art.

Thus, in Scheme 3, step 1, the diamino compound, 8 is contacted withcarbon disulfide under suitable reaction conditions to form theimidazoline-2-thione derivative, 9. The cyclization can be effected byany of the procedures known in the art. Typically, this reaction iscarried out at an elevated temperature in the range of from about 80° C.to 100° C. preferably in the presence of a suitable solvent such asabsolute ethanol and the like.

In Scheme 3, step 2, the imidazoline-2-thione derivative, 9 ismethylated using any of the known methylating agents such as methyliodide to form the thiomethyl derivative, 10, which is further contactedwith a suitable protective agent to form the N-protected derivative, 11.Various N-protecting groups that are known in the art can be employed inthis step, see for example, Protecting Groups in Organic Synthesis by T.Greene, John Wiley & Sons, Inc., 2^(nd) Ed., 1991. Scheme 2, step 3,shows the N-protection using tert-butoxycarbonyl (Boc) group. This canbe effected by treating the thiomethyl derivative, 10 withdi-tert-butyl-dicarbonate. This N-protection reaction is typicallycarried out in the presence of a base such as triethylamine and4-dimethylamino-pyridine (DMAP) in a suitable organic solvent such asdichloromethane.

In Scheme 3, step 4, the N-protected thiomethyl-imidazoline derivative,11 is reacted with a desirable amino compound to form theN-protected-2-amino-imidazoline derivative, 12. This reaction cangenerally be carried out using any of the methods known in the art. Forexample, the derivative, 11 is contacted with a suitable amine in an artrecognized solvent such as methanol or ethanol at a suitable reactiontemperature. In general, the suitable reaction temperature is in therange of from about 80° C. to 120° C., however, lower or highertemperatures can be utilized depending upon the imidazoline compound, 11and the amino compound that are being employed. Finally, the Boc groupis cleaved suitably under acidic reaction conditions such ashydrochloric acid to form the 2-aminosubstituted imidazoline, 13.Alternatively, in certain reaction conditions, the thiomethylimidazoline, 11 can be aminated and the protective group is cleaved inthe same step to form the 2-aminosubstituted imidazoline, 13 as shown instep 4A.

Scheme 4 illustrates an alternative method for the preparation ofcertain N-substituted imidazoline compounds of this invention. Thisapproach is particularly suitable for those compounds in which X—Y is—NHCO—.

In Scheme 4, step 1, the N-protected thiomethyl derivative, 14 isprepared in an analogous manner as described above for the preparationof derivative, 11. The thiomethyl derivative, 14 is then contacted withammonia to form the 2-amino imidazoline compound, 15. This reaction canbe carried out using any of the procedures known in the art. Forexample, the amination can be carried out by reacting the N-protectedthiomethyl derivative, 14 with ammonia in an organic solvent such asethylene glycol under pressure at a temperature in the range of fromabout 100° C. to 130° C. Generally, in this step the N-protected groupis also cleaved. Thus, in Scheme 4, step 2, the nitrogen of theimidazoline ring is again protected using the Boc group as describedabove.

In Scheme 4, step 3, the amino group is amidated using any of the knowncarboxylating agents. For example, this reaction can be convenientlycarried out using a carboxylic acid chloride in the presence of asuitable acid acceptor such as triethylamine. Additional acylating agentactivators or a base can be employed such as for example DMAP. Thereaction is typically carried out in aprotic organic solvents such asdichloromethane or a hydrocarbon solvent such as hexanes, petroleumether or mixtures thereof. Finally, the N-protecting group is removed inScheme 4, step 4 as described above.

Scheme 5 illustrates preparation of various imidazoline compounds ofthis invention wherein X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)— and wherein Z isO, S NR₆, or Z is a bond, and a is 0 or 1 and b is 1 or 2. This approachis particularly suitable for those compounds in which a is 1.

In Scheme 5, the starting 1,2-diaminoethane derivative, 8B can beprepared following the procedures of scheme 2B. The diamine, 8B is thencontacted with a carboxylic acid ester derivative, 19 to form theimidazoline compound, 20. In carboxylic acid derivative, 19, R_(d) isC₁₋₄ alkyl, preferably methyl or ethyl. The condensation of 8B with 19can be carried out using any of the procedures known in the art.However, it has now been found that contacting of 8B with 19 in thepresence of an alkyl aluminum reagent such as trimethylaluminum providesa convenient method for the preparation of 20. The condensation cantypically be carried out in a hydrocarbon solvent such as toluene in aninert atmosphere at a temperature in the range of from about 50° C. to80° C. The condensation reaction can also be carried out using variousother carboxylic acid ester equivalents such as nitrites, carboxylicacid halides, preferably chlorides or bromides, carboxylic acidanhydrides, mixed anhydrides of carboxylic acids, and the like. One suchexample of condensation reaction with nitrites is shown in Scheme 5A.

The reaction shown in Scheme 5A is particularly useful for thepreparation of imidazoline compound, 20, wherein Z is O, a is 1 and b is0. The reaction is carried out essentially under similar conditions asdescribed above for Scheme 5.

In Scheme 6, the imidazoline thione, 9A is converted to an imidazolinecompound, 21 of this invention, wherein X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—in which Z is S and a is 0. The starting compound, 9A can be synthesizedfollowing the procedures set forth for the preparation of intermediate,9 in Scheme 3 above and employing the 1,2-diaminoethane compound, 8B.

In general, the imidazoline thione, 9A is contacted with a halidecompound such as R₅(CH₂)_(b)Cl in a suitable organic solvent preferablyat elevated temperatures to form the product, 21. Suitable organicsolvents include alcohols such as ethanol or halogenated solvents suchas ethylene chloride and mixtures thereof, ethanol being the preferredsolvent. The reaction is suitably carried out at a temperature range offrom about 80° C. to 100° C.

Scheme 7 illustrates another method for the preparation of imidazolinecompounds, 23 in which X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)— in which Z is abond and a is 0. In Scheme 7, step 1, one of the starting materials, thenitrile intermediate, 23 is prepared by treating a desirable nitrilecompound, 22 with methanol in the presence of a suitable acid such ashydrochloric acid.

In Scheme 7, step 2, the intermediate, 23 is then reacted with1,2-diaminoethane compound, 8B preferably at superambient temperaturesto form the imidazoline compound, 24 of this invention. This reaction isgenerally carried out in an alcoholic solvent such as ethanol in thetemperature range of from about 80° C. to 100° C.

Scheme 8 shows preparation of a specific class of imidazoline compoundsof this invention in which X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)— and in which Zis a bond and a is 0, and b is 2, and R₅ is phenyl or substitutedphenyl, wherein R_(a) is any of the suitable substituent as definedherein. Additionally, one of the methylene groups is substituted with ahydroxy group.

In Scheme 8, the compound 25 can be prepared following the procedures ofscheme 7 and employing acetonitrile as the starting nitrile compound,22. The nitrogen atom of the imidazoline compound, 25 is then protectedwith tert-butoxycarbonyl (Boc) using the procedures as described above.The N-protected imidazoline compound, 26 is then contacted with acarbanion donor such as n-butyl lithium and the resulting anion of 26 isreacted with benzaldehyde or substituted benzaldehyde. This reaction isgenerally carried out at subambient temperature conditions such as forexample in the temperature range of from about −70° C. to −40° C.,usually in an inert atmosphere of nitrogen or argon. The resultingproduct, 27 is then contacted with a suitable acid to remove theN-protecting group to form the imidazoline compound, 28.

The imidazoline compounds of this invention can also be prepared by anyof the solid phase synthesis known in the art. Optionally, the solidphase synthesis can also involve any of the known parallel orcombinatorial methods such that a wide array of imidazoline compoundscan be prepared. One such solid phase approach is shown in Scheme 9.

In Scheme 9, the 1,2-diaminoethane compound, 8B is reacted with a solidphase resin to form the intermediate 29, which is then condensed with adesirable carboxylic acid to form the imidazoline compound, 32.Variations of this approach can be employed to prepare various otherimidazoline compounds as described herein. More specifically, theimidazoline compounds prepared in accordance with Schemes 1-8 can alsobe prepared using a solid phase method and utilizing similar steps asset forth therein.

In an analogous fashion N-substituted imidazoline compounds of thisinvention can also be synthesized using a procedure that is very similarto the one depicted in Scheme 9. This is illustrated in Scheme 9A.

In Scheme 9A, the 1,2-diaminoethane compound, 8B is reacted first with asolid phase resin to form the intermediate 29, which is subsequentlyreacted with a desirable aldehyde in the presence of a suitable reducingagent such as sodium cyanoborohydride in the presence of an acid such asacetic acid and a suitable solvent or a solvent mixture (e.g.,dichloromethane, trimethylorthoformate (TMOF) or mixtures thereof andthe like). The N-substituted compound, 30A is then cleaved-off from thesolid resin as described herein to obtain compound, 31A which in turn iscondensed with a suitable one carbon containing condensating agent suchas ethyl formimidate hydrochloride or any other known condensating agentto form the N-substituted imidazoline compound, 32A.

Scheme 10 illustrates a preparation of a specific class of imidazolinecompounds of this invention in which substituents R₁ and R₃ aredifferent. Thus following the series of steps as set forth in Scheme 10,the 1,2-diamino-ethane, 37 can be prepared. In an analogous mannervarious other 1,2-diamino-ethane compounds can be prepared by startingwith the appropriate starting carboxylic acid, 33 and the Grignardreagent. The diamine, 37 is then condensed with the desired carboxylicacid derivative, 38 to form the imidazoline compound, 39 of thisinvention, in which R₅, Z, R_(a), a and b are as defined herein. Thecondensation of 37 with 38 can be carried out using the procedures asdescribed in Scheme 5. Additionally any of the known carboxylic acidequivalents as described above can be employed in place of carboxylicacid ester, 37, see Scheme 5A.

Finally, Scheme 11 shows N-substitution reaction to form theN-substituted imidazoline derivatives of this invention. Any of theN-substitution reactions known in the art can be employed in thismethod. Thus, the imidazoline compound, IIA prepared in accordance withany of the procedures set forth in Schemes 1-10 is reacted with suitablereagent, R-Hal, to form the N-substituted compound, II of this inventionwherein R is as defined herein other than hydrogen. The reagent, R-Hal,is any reagent known in the art which is suitable for a N-substitutionreaction. Thus, Hal is preferably a halogen such as chlorine or bromine,but any other suitable leaving group can be used. For example, theimidazoline compound can be reacted with acylating reagents such ascarboxylic acid chloride to form N-amide derivative. Similarly, reactionwith a wide variety of chloroformates results in carbamate derivativesand reaction with alkyl or aryl halides results in alkyl or arylderivatives.

In another aspect of this invention there is also provided a method forthe treatment of diseases selected from the group consisting ofinflammatory bowel disease, rheumatoid arthritis, and diseasesassociated with central nervous system, which comprises administering toa patient in need of such treatment a therapeutically effective amountof a compound of the formula (II):

-   -   wherein:    -   R is hydrogen, C₁₋₆ alkyl, C₂₋₆ acyl, C₁₋₆ alkoxycarbonyl, or        C₆₋₁₂ aryloxycarbonyl;    -   R₁ and R₃ are the same or different and are each independently        selected from:        -   C₅₋₈ cycloalkyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, tetrahydrofuranyl,            tetrahydropyranyl, tetrahydrothiophenyl or thiazolinyl,        -   aryl, selected from phenyl, biphenyl or naphthyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   aryl C₁₋₄ alkyl, C₅₋₈ cycloalkyl C₁₋₄ alkyl, heteroaryl C₁₋₄            alkyl, wherein aryl and heteroaryl are as defined above, and        -   wherein C₅₋₈ cycloalkyl, aryl or heteroaryl is optionally            substituted with one or more substituents selected from the            group consisting of halogen, C₁₋₄ alkyl, fluoroalkyl or            fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H,        -   —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; or    -   R₁ and R₃ taken together with the carbon atoms to which they are        attached form a cyclopentane, cyclohexane, cycloheptane or        cyclooctane;    -   R₂ and R₄ are the same or different and are each independently        selected from:        -   hydrogen, C₁₋₆ alkyl or fluoroalkyl of the formula            C_(n)H_(x)F_(y), wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1;    -   R₅ is hydrogen, C₃₋₈ cycloalkyl, C₂₋₄ alkynyl,        -   heterocyclyl, selected from morpholinyl, piperidinyl,            piperazinyl, pyrrolidinyl, pyridinonyl, tetrahydrofuranyl,            tetrahydropyranyl, dioxanyl, benzopyranyl,            dihydrobenzodioxanyl, tetrahydrothiophenyl or thiazolinyl,            aryl, selected from phenyl, biphenyl, naphthyl or            anthracenyl,        -   heteroaryl, selected from benzimidazolyl, benzofuranyl,            benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl,            isoquinolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,            pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl,            tetrazolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl,        -   wherein C₅₋₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is            optionally substituted with one or more substituents            selected from the group consisting of halogen, C₁₋₄ alkyl,            fluoroalkyl fluoroalkoxy of the formula C_(n)H_(x)F_(y) or            OC_(n)H_(x)F_(y) wherein n is an integer from 1 to 4, x is            an integer from 0 to 8, y is an integer from 1 to 9 and sum            of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,            C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄            dialkylamino, amino C₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl,            C₁₋₄ dialkylamino C₁₋₄ alkyl, —CN, —CO₂H, —CO₂C₁₋₄ alkyl,            phenyl, phenoxy and benzyloxy;    -   X—Y is —(CH₂)_(a)—Z—(CH₂)_(b)—, —(CH₂)_(a)—Z—(CH₂)_(b)—Z¹— or        —NHCO—, wherein        -   wherein (CH₂) is optionally substituted with one or more            groups selected independently from:        -   hydroxy, C₁₋₆ alkoxy, arylaminocarbonyloxy, C₃₋₈ cycloalkyl,            C₁₋₆ alkyl or fluoroalkyl of the formula C_(n)H_(x)F_(y),            wherein n is an integer from 1 to 4, x is an integer from 0            to 8, y is an integer from 1 to 9 and sum of x and y is            2n+1, wherein said alkoxy or alkyl or fluoroalkyl is            optionally substituted with at least one substituent            selected from the group consisting of: hydroxy, —SH, C₁₋₄            alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   Z and Z¹ are the same or different and are each            independently selected from:        -   O, S, NR₆, NR₆—NR₆, —OCONH—, —NH—CO—NH—, —SO₂—NH—,            —(NR₆)SO₂— or        -   a bond,        -   wherein R₆ is selected from:        -   hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl or fluoroalkyl of the            formula C_(n)H_(x)F_(y), wherein n is an integer from 1 to            4, x is an integer from 0 to 8, y is an integer from 1 to 9            and sum of x and y is 2n+1, wherein said alkoxy or alkyl or            fluoroalkyl is optionally substituted with at least one            substituent selected from the group consisting of: hydroxy,            —SH, C₁₋₄ alkoxy,        -   C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,        -   C₁₋₄ dialkylamino, —CN, —CO₂H, and —CO₂C₁₋₄ alkyl, aryl;        -   a is an integer from 0 to 2 and b is an integer from 0 to 4            provided that sum of a and b is at least 1            or a pharmaceutically acceptable salt thereof, optionally in            combination with a pharmaceutically acceptable carrier.

In a specific embodiment of the method of this invention the diseasethat can be effectively treated with the compounds of this invention isinflammatory bowel disease. In another embodiment the disease state thatcan be treated in accordance with the method of this invention isrheumatoid arthritis.

In another embodiment various disease states that are associated withcentral nervous system (CNS) can be treated using the compounds of thisinvention. Specific CNS disease conditions include, but not limited to,stroke, Alzheimer's disease, multiple sclerosis, septic shock and headtrauma.

All of the preferred embodiments of the compounds of this invention asdisclosed herein can be used in the method of treating various diseasestates as described herein. As stated herein, the compounds of thisinvention are capable of antagonizing the effects of P2X7 receptor andthereby alleviating the inflammatory effects caused due to the P2X7receptors. In another embodiment of the method of this invention thecompounds of this invention can be administered by any of the methodsknown in the art. Specifically, the compounds of this invention can beadministered by oral, intramuscular, subcutaneous, rectal,intratracheal, intranasal, intraperitoneal or topical route.

In yet another aspect of this invention there is also provided apharmaceutical composition comprising a compound or a pharmaceuticallyacceptable salt thereof in combination with at least onepharmaceutically acceptable carrier for treating diseases selected fromthe group consisting of inflammatory bowel disease, rheumatoidarthritis, and diseases associated with central nervous system, whereinsaid compound is of the formula (II) as described herein, including thepharmaceutically acceptable salt thereof, optionally in combination witha pharmaceutically acceptable carrier. In this aspect of the inventionall of the compounds encompassing the generic scope of the formula (II)are used in the composition of this invention.

In a specific embodiment of the composition of this invention thedisease that can be effectively treated with the composition of thisinvention is inflammatory bowel disease. In another embodiment thedisease state that can be treated in accordance with the composition ofthis invention is rheumatoid arthritis.

In another embodiment various disease states that are associated withcentral nervous system (CNS) can be treated using the compositions ofthis invention. As stated herein, specific CNS disease conditionsinclude, but not limited to, stroke, Alzheimer's disease, multiplesclerosis, septic shock and head trauma.

All of the preferred embodiments of the compounds of this invention asdisclosed herein can be used in preparing the pharmaceuticalcompositions as described herein. As stated herein, the pharmaceuticalcompositions comprising the compounds of this invention are capable ofantagonizing the effects of P2X7 receptor and thereby alleviating theinflammatory effects caused due to the P2X7 receptors.

Preferably the pharmaceutical compositions of this invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,sterile parenteral solutions or suspensions, metered aerosol or liquidsprays, drops, ampoules, auto-injector devices or suppositories; fororal, parenteral, intranasal, sublingual or rectal administration, orfor administration by inhalation or insufflation. Alternatively, thecompositions may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. An erodible polymercontaining the active ingredient may be envisaged. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of the present invention. Flavored unitdosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50or 100 mg, of the active ingredient. The tablets or pills of the novelcomposition can be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered byany of the methods known in the art. In general, the pharmaceuticalcompositions of this invention can be administered by oral,intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route. The preferred administration of thepharmaceutical composition of this invention is by an intranasal route.Any of the known methods to administer pharmaceutical compositions by anintranasal route can be used to administer the composition of thisinvention.

In the treatment of various disease states as described herein, asuitable dosage level is about 0.01 to 250 mg/kg per day, preferablyabout 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kgper day. The compounds may be administered on a regimen of 1 to 4 timesper day.

This invention is further illustrated by the following examples whichare provided for illustration purposes and in no way limit the scope ofthe present invention.

EXAMPLES General

As used in the examples and preparations that follow, the terms usedtherein shall have the meanings indicated: “kg” refers to kilograms, “g”refers to grams, “mg” refers to milligrams, “μg” refers to micrograms,“pg” refers to picograms, “mol” refers to moles, “mmol” refers tomillimoles, “nmole” refers to nanomoles, “L” refers to liters, “mL” or“ml” refers to milliliters, “μL” refers to microliters, “° C.” refers todegrees Celsius, “R_(f)” refers to retention factor, “mp” or “m.p.”refers to melting point, “dec” refers to decomposition, “bp” or “b.p.”refers to boiling point, “mm of Hg” refers to pressure in millimeters ofmercury, “cm” refers to centimeters, “nm” refers to nanometers, “abs.”refers to absolute, “conc.” refers to concentrated, “[α]²⁰ _(D)” refersto specific rotation of the D line of sodium at 20° C. obtained in a 1decimeter cell, “c” refers to concentration in g/mL, “THF” refers totetrahydrofuran, “DMF” refers to dimethylformamide, “NMP” refers to1-methyl-2-pyrrolidinone, “brine” refers to a saturated aqueous sodiumchloride solution, “M” refers to molar, “mM” refers to millimolar, “μM”refers to micromolar, “nM” refers to nanomolar, “TLC” refers to thinlayer chromatography, “HPLC” refers to high performance liquidchromatography, “HRMS” refers to high resolution mass spectrum, “lb”refers to pounds, “gal” refers to gallons, “L.O.D.” refers to loss ondrying, “μCi” refers to microcuries, “i.p.” refers to intraperitoneally,“i.v.” refers to intravenously.

General Analytical Techniques Used for the Characterization: A varietyof analytical techniques are used to characterize and isolate thecompounds of this invention, which included the following:

The phrase “concentrated in vacuo or rotary evaporated” indicates rotaryevaporation using a Buchi apparatus at 20-60° C. and 15-30 torr using aKNF Neuberger diaphragm pump. Room temperature is abbreviated as “RT”.

Preparative reversed phase HPLC was carried out on a Rainin SD1 unitusing a Dynamax C₁₈ column (60 A spherical 13 μm particles). The mobilephase consisted of acetonitrile/buffer mixtures, with buffer composed ofdistilled water, acetonitrile, and trifluoroacetic acid (TFA) in theratio listed in the experimental procedures.

¹H NMR spectra were recorded on a Varian Gemini 300, Unity 300, Unity400, or Unity 500 spectrometers with chemical shifts (6) reported in ppmrelative to tetramethylsilane (0.00 ppm) or chloroform (7.26 ppm) as areference. Signals were designated as s (singlet), d (doublet), t(triplet), q (quartet), p (pentuplet), m (multiplet), br (broad).

Chromatographic (flash) purifications on silica gel were done usingpre-packed Isco or Biotage cartridges (32-63 μm, 60 A).

Mass spectra (MS) were obtained on a Finnigan MAT Model TSQ 700 MassSpectrometer System by chemical ionization at 120 eV using methane (CI,120 eV). The protonated molecular ion designated as (M⁺+1) is given inparentheses.

Liquid chromatography with mass spectral analysis (LC/MS): HPLC: column:50×4.6 mm, Hypersil BDS C18 3u. Mobile Phase: A=water with 0.05%trifluoroacetic acid, B=acetonitrile with 0.05% trifluoroacetic acid,flow rate=1.0 ml/min, gradient=5% B to 100% B in 3 min, stay 100% for 2min. Mass Spectrometry: Lct API LC/Orthogonal Time of Flight MassSpectrometer and Masslynx Data System from Micromass. Ionizationmode=electrospray (ESI), Source temperature=120° C., Desolvationtemperature=250° C., Cone voltage=25 volt, Acquisition mass range nm/zfrom 145 to 1000. Values were determined for the protonated molecularions (M⁺+1).

Several of the intermediates unless otherwise mentioned were obtained bya variety of commercial sources. For instance,meso-1,2-diphenylethane-1,2-diamine (1);(1S,2S)-(−)-diphenylethane-1,2-diamine (2);(1R,2R)-(+)-diphenylethane-1,2-diamine (3); cis-1,2-diaminocyclohexane(24) were purchased from Aldrich Chemical Co. Various otherintermediates used in the syntheses of the compounds of this inventionwere prepared in accordance with the procedures set forth in thefollowing Preparations 1 to 67.

Preparation 1 meso-1,2-bis-(2-Fluorophenyl)ethane-1,2-diamine (4)

A mixture of 2-fluororobenzaldehyde (40 mL, 0.38 mol) and ammoniumacetate (85.0 g, 1.1 mol) is heated at 130° C. for 6 h and then at 100°C. overnight. The mixture is cooled to RT, suspended in abs. EtOH andfiltered. The filter cake is washed with abs. EtOH and with 95% EtOH.The crude intermediate,2-fluoro-N-[2-[(2-fluorobenzylidine)amino]-1,2-cis-bis-(2-fluorophenyl)ethyl]benzamide(28.9 g), is used in the next step without further purification.

The crude intermediate (5.0 g, 10.5 mmol) is suspended in 50% H₂SO₄/H₂O(50 mL) and heated at 180° C. overnight. Water (5 mL portions) is addedevery 30 min for the first 2 h. The reaction mixture is cooled (icebath), and water is added slowly. The solution is extracted with ether.The cold aqueous layer is basified with conc. NH₄OH, and extracted withether. The combined ether extracts are dried (MgSO₄), filtered, andconcentrated in vacuo to yield 2.6 g of the product 4. ¹H NMR (CDCl₃) δ7.40-7.30 (m, 2 H), 7.30-7.20 (m, 2 H), 7.20-7.10 (m, 2 H), 7.10-7.00(m, 2 H), 4.45 (s, 2 H), 1.47 (s, 4 H); MS: m/z 249 (M⁺+1).

Preparation 2 meso-1,2-bis-(3-Fluorophenyl)ethane-1,2-diamine (5)

A mixture of 3-fluororobenzaldehyde (45.38 g, 0.37 mol) and ammoniumacetate (92.0 g, 1.2 mol) is heated at 130° C. overnight. The mixture iscooled to RT, suspended in abs. EtOH and filtered. The filter cake iswashed with abs. EtOH and with 95% EtOH. The crude intermediate,3-fluoro-N-[2-[(3-fluorobenzylidine)amino]-1,2-cis-bis-(3-fluorophenyl)-ethyl]benzamide(39.7 g) is used in the next step without further purification.

The crude intermediate (30.0 g, 63 mmol) is suspended in 50% H₂SO₄/H₂O(300 mL) and heated at 170° C. for 10 h. Water (5 mL portions) is addedevery 30 min for the first 2 h. The reaction mixture is cooled (icebath), and water is added slowly. The solution is extracted with ether.The cold aqueous layer is basified with conc. NH₄OH, and extracted withether. The combined ether extracts are dried (MgSO₄), filtered, andconcentrated in vacuo to yield 14.6 g of the product 5. ¹H NMR (CDCl₃) δ7.35-7.25 (m, 2 H), 7.15-7.05 (m, 4 H), 7.05-6.95 (m, 2 H), 4.02 (s, 2H), 1.34 (s, 4 H); MS: m/z 249 (M⁺+1).

Preparation 3 meso-1,2-bis-(4-Fluorophenyl)ethane-1,2-diamine (6)

A mixture of 4-fluororobenzaldehyde (117.8 g, 0.95 mol) and ammoniumacetate (204 g, 2.64 mol) is heated at 130° C. for 5 h. The mixture iscooled to RT, suspended in abs. EtOH and filtered. The filter cake iswashed with abs. EtOH and with 95% EtOH. The crude intermediate,4-fluoro-N-[2-[(4-fluorobenzylidine)amino]-1,2-cis-bis-(4-fluorophenyl)-ethyl]benzamide(80.8 g) is used in the next step without further purification.

The crude intermediate (30 g, 63 mmol) is suspended in 50% H₂SO₄/H₂O(300 mL) and heated at 180° C. for 7 h. The reaction mixture is cooled(ice bath), and water (150 mL) is added slowly. The solution isextracted with ether. The cold aqueous layer is basified with conc.NH₄OH, and extracted with ether. The combined ether extracts are dried(MgSO₄), filtered, and concentrated in vacuo to yield 8.14 g of theproduct 6. ¹H NMR (CDCl₃) δ 7.40-7.30 (m, 4 H), 7.10-7.00 (m, 4 H), 3.99(s, 2 H), 1.52 (s, 4 H); MS: m/z 249 (M⁺+1).

Preparation 4 meso-1,2-bis-(2-Chlorophenyl)ethane-1,2-diamine (7)

A mixture of 2-chlorobenzaldehyde (117.8 g, 0.95 mol) and ammoniumacetate (204 g, 2.64 mol) is heated at 130° C. overnight. The mixture iscooled to RT, suspended in abs. EtOH and filtered. The filter cake iswashed with abs. EtOH and with 95% EtOH. The crude intermediate,2-chloro-N-[2-[(2-chlorobenzylidine)amino]-1,2-cis-bis-(2-chlorophenyl)-ethyl]benzamide(80.8 g) is used in the next step without further purification

The crude intermediate (30 g, 63 mmol) is suspended in 50% H₂SO₄/H₂O(300 mL) and heated at 180° C. for 7 h. The reaction mixture is cooled(ice bath), and water is added slowly. The solution is extracted withether. The cold aqueous layer is basified with conc. NH₄OH, andextracted with ether. The combined ether extracts are dried (MgSO₄),filtered, and concentrated in vacuo to yield 8.14 g of the product 7.

Preparation 5 meso-1,2-bis-(3-Chlorophenyl)ethane-1,2-diamine (8)

A mixture of 3-chlorobenzaldehyde (50 g, 0.36 mol) and ammonium acetate(77 g, 1.0 mol) is heated at 130° C. overnight. The mixture is cooled toRT, suspended in abs. EtOH and filtered. The filter cake is washed withabs. EtOH and with 95% EtOH. The crude intermediate,3-chloro-N-[2-[(3-chlorobenzylidine)amino]-1,2-cis-bis-(3-chlorophenyl)-ethyl]benzamide(34.3 g) is used in the next step without further purification

The crude intermediate (30 g, 55 mmol) is suspended in 50% H₂SO₄/H₂O(300 mL) and heated at 180° C. for 7 h. The reaction mixture is cooled(ice bath), and water is added slowly. The solution is extracted withether. The cold aqueous layer is basified with conc. NH₄OH, andextracted with ether. The combined ether extracts are dried (MgSO₄),filtered, and concentrated in vacuo to yield 8.14 g of the product 8.

Preparation 6 meso-1,2-bis-(4-Chlorophenyl)ethane-1,2-diamine (9)

A mixture of 4-chlorobenzaldehyde (138 g, 0.98 mol) and ammonium acetate(276 g, 3.58 mol) is heated at 130° C. overnight. The mixture is cooledto RT, suspended in abs. EtOH and filtered. The filter cake is washedwith abs. EtOH and with 95% EtOH. The crude intermediate,4-chloro-N-[2-[(4-chlorobenzylidine)amino]-1,2-cis-bis-(4-chlorophenyl)-ethyl]benzamide(107 g) is used in the next step without further purification.

The crude intermediate (107 g, 0.193 mol) is suspended in 50% H₂SO₄/H₂O(500 mL) and heated at 180° C. for 10 h. The reaction mixture is cooled(ice bath), and water is added slowly. The solution is extracted withether. The cold aqueous layer is basified with conc. NH₄OH, andextracted with ether. The combined ether extracts are dried (MgSO₄),filtered, and concentrated in vacuo to yield 38.1 g of the product 9. ¹HNMR (CDCl₃) δ 7.35-7.15 (m, 8 H), 3.97 (s, 2 H), 1.38 (s, 4 H); MS: m/z281 (M⁺+1).

Preparation 7 meso-1,2-bis-(2-Bromophenyl)ethane-1,2-diamine (10)

A mixture of 2-bromobenzaldehyde (45 g, 0.24 mol) and ammonium acetate(90 g, 1.2 mol) is heated at 130° C. overnight. The mixture is cooled toRT, and the gummy yellow residue is washed with heptane. The crudeintermediate,2-bromo-N-[2-[(2-bromo-benzylidine)amino]-1,2-cis-bis-(2-bromophenyl)ethyl]benzamide,is used in the next step without further purification.

The crude intermediate from above is suspended in 50% H₂SO₄/H₂O (400 mL)and heated at 170° C. overnight. The reaction mixture is cooled (icebath), and water (200 mL) is added slowly. The solution is extractedwith ether. The cold aqueous layer is basified with conc. NH₄OH, andextracted with ether. The combined ether extracts are dried (MgSO₄),filtered, and concentrated in vacuo to yield the product 10.

Preparation 8 meso-1,2-bis-(2-Methylphenyl)ethane-1,2-diamine (11)

A mixture of 2-methylbenzaldehyde (100 g, 0.83 mol) and ammonium acetate(200 g, 2.6 mol) is heated at 135° C. overnight. The mixture is cooledto RT, suspended in abs. EtOH and filtered. The filter cake is washedwith abs. EtOH. The crude intermediate,2-methyl-N-[2-[(2-methylbenzylidine)amino]-1,2-cis-bis-(2-methylphenyl)ethyl]-benzamide(34.7 g) is used in the next step without further purification.

The crude intermediate (34.2 g, 70 mmol) is suspended in 50% H₂SO₄/H₂O(200 mL) and heated at 180° C. for 5 h and then at 150° C. overnight.The reaction mixture is cooled (ice bath), and water (100 mL) is addedslowly. The solution is extracted with ether. The cold aqueous layer isbasified with conc. NH₄OH, and extracted with ether. The combined etherextracts are dried (MgSO₄), filtered, and concentrated in vacuo to yield13.6 g of the product 11. ¹H NMR (CDCl₃) δ 7.45-7.35 (m, 2 H), 7.30-7.10(m, 6H), 4.44 (s, 2 H), 2.31 (s, 6 H), 1.44 (s, 4 H); MS: m/z 241(M⁺+1).

Preparation 9 meso-1,2-bis-(3-Methylphenyl)ethane-1,2-diamine (12)

A mixture of 3-methylbenzaldehyde (100 g, 0.83 mol) and ammonium acetate(200 g, 2.6 mol) is heated at 130° C. overnight. The mixture is cooledto RT, suspended in abs. EtOH and filtered. The filter cake is washedwith abs. EtOH and with 95% EtOH. The crude intermediate,3-methyl-N-[2-[(3-methylbenzylidine)amino]-1,2-cis-bis-(3-methyl-phenyl)-ethyl]benzamide(81.2 g) is used in the next step without further purification.

The crude intermediate (79.7 g, 173 mmol) is suspended in 50% H₂SO₄/H₂O(200 mL) and heated at 180° C. for 5 h. The reaction mixture is cooled(ice bath), and water (200 mL) is added slowly. The solution isextracted with ether. The cold aqueous layer is basified with conc.NH₄OH, and extracted with ether. The combined ether extracts are dried(MgSO₄), filtered, and concentrated in vacuo to yield 5.18 g of theproduct 12. ¹H NMR (CDCl₃) δ 7.35-7.20 (m, 6 H), 7.15-7.10 (m, 2 H),3.96 (s, 2 H), 2.37 (s, 6 H), 1.43 (s, 4 H); MS: m/z 241 (M⁺+1).

Preparation 10 meso-1,2-bis-(4-Methylphenyl)ethane-1,2-diamine (13)

A mixture of 4-methylbenzaldehyde (100 mL, 0.85 mol) and ammoniumacetate (200 g, 2.6 mol) is heated at 130° C. overnight. The mixture iscooled to RT, suspended in abs. EtOH and filtered. The filter cake iswashed with abs. EtOH and with 95% EtOH. The crude intermediate,4-methyl-N-[2-[(4-methylbenzylidine)amino]-1,2-cis-bis-(4-methylphenyl)-ethyl]benzamide(68.2 g) is used in the next step without further purification.

The crude intermediate (67.8 g, 147 mmol) is suspended in 50% H₂SO₄/H₂O(500 mL) and heated at 180° C. overnight. The reaction mixture is cooled(ice bath), and water (200 mL) is added slowly. The solution isextracted with ether. The cold aqueous layer is basified with conc.NH₄OH, and extracted with ether. The combined ether extracts are dried(MgSO₄), filtered, and concentrated in vacuo to yield 7.83 g of theproduct 13.

Preparation 11 cis-1,2-Diphenylpropane-1,2-diamine (16)

Step 1

3,4-Diphenyl-1,2,5-thiadiazole-1,1-dioxide (14)

Hydrogen chloride is bubbled through a solution of benzil (24 g, 0.11mmol) and sulfamide (11 g, 0.11 mmol) in methanol (120 mL) for 2 hfollowed by heating to reflux for 2 h. The reaction mixture is cooled toRT, and the precipitate that formed is filtered to give 25.1 g of theproduct 14.

Step 2

cis-3,4-Diphenyl-3-methyl-2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide (15)

To a cool (10° C.) suspension of 14 (25 g, 92 mmol) in toluene:THF(300:60 mL) is added 3.0M methylmagnesium bromide in Et₂O (35 mL, 105mmol), and the mixture is stirred at ambient temperature for 1 h. Thereaction mixture is quenched with saturated ammonium chloride, extractedwith EtOAc, and the organic extract is washed with brine, dried (MgSO₄),filtered, and the filtrate rotary evaporated. The residue is dissolvedin methanol (250 mL), cooled to 0° C., and sodium borohydride (9 g, 238mmol) is added portionwise. The mixture is stirred at ambienttemperature for 45 min, cooled to 0° C., and 5M HCl is added to bringthe solution to pH 2. The mixture is extracted with EtOAc, and theorganic extract is washed with brine, dried (MgSO₄), filtered, and thefiltrate rotary evaporated. The residue is crystallized from toluene togive 20.4 g of the product 15.

Step 3

cis-1,2-Diphenylpropane-1,2-diamine (16)

A suspension of 15 (20.4 g, 70 mmol) in 2M HBr (500 mL) containingphenol (32 g) is stirred and heated at reflux for 40 h. The mixture iscooled to RT, extracted with EtOAc, and the aqueous solution is cooled(ice bath) and made basic with sodium hydroxide. The basic solution isextracted with Et₂O, and the extract dried (Na₂SO₄), filtered, and thefiltrate rotary evaporated to give 11.1 g of the product 16.

Preparation 12 cis-1,2-bis-(4-Fluorophenyl)propane-1,2-diamine (19)

Step 1

3,4-bis-4-(Fluorophenyl)-1,2,5-thiadiazole-1,1-dioxide (17)

Hydrogen chloride is bubbled through a solution of 4,4′-difluorobenzil(5.0 g, 20.3 mmol) and sulfamide (2.67 g, 27.8 mmol) in methanol (20 mL)for 0.5 min followed by heating to reflux for 2 h. The reaction mixtureis cooled to RT, and the precipitate that formed is filtered to give 3 gof the product 17.

Step 2

cis-3,4-bis-(4-Fluorophenyl)-3-methyl-2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide(18)

To a cool (10° C.) suspension of 17 (2.2 g, 7.19 mmol) in toluene:THF(60:6 mL) is added 3.0M methylmagnesium bromide in Et₂O (3.59 mL, 10.8mmol), and the mixture is stirred at ambient temperature for 1 h. Thereaction mixture is quenched with saturated ammonium chloride, extractedwith EtOAc, and the organic extract is dried (Na₂SO₄), filtered, and thefiltrate rotary evaporated. The residue is dissolved in methanol (20mL), cooled to 0° C., and sodium borohydride (1.08 g, 28.5 mmol) isadded portionwise. The mixture is stirred at 20° C. for 45 min, cooledto 0° C., and 5M HCl is added to bring the solution to pH 2. The mixtureis extracted with EtOAc, and the organic extract is washed with brine,dried (Na₂SO₄), filtered, and the filtrate rotary evaporated. Theresidue is dissolved in EtOAc, and the addition of heptane precipitates1.5 g of the product 18.

Step 3

cis-1,2-bis-(4-Fluorophenyl)propane-1,2-diamine (19)

A suspension of 18 (1.5 g, 4.6 mmol) in 2M HBr (56 mL) containing phenol(2.17 g) is stirred and heated at reflux for 24 h. The mixture is cooledto RT, extracted with EtOAc, and the aqueous solution is cooled (icebath) and made basic with sodium hydroxide. The basic solution isextracted with EtOAc:Et₂O (1:1), and the extract is washed with brine,dried (Na₂SO₄), filtered, and the filtrate rotary evaporated to give 0.7g of the product 19.

Preparation 13 cis-1,2-bis-(3-Fluorophenyl)propane-1,2-diamine (23)

Step 1

3,3′-Difluorobenzil (20)

To anhydrous THF (80 mL) is added magnesium (2.9 g, 0.120 mol) and1-bromo-3-fluorobenzene (12.76 g, 0.114 mol) in anhydrous THF (30 mL).The mixture is stirred at 21° C. for 1.5 h. To THF (60 mL) is addedlithium bromide (13.22 g, 0.015 mol) and copper (I) bromide (10.9 g,0.0762 mol) and the mixture is stirred at RT until homogenous, thencooled to 0° C. To this solution is added 3-fluorophenylmagnesiumbromide solution followed by a solution of oxalyl chloride (2.76 mL,0.0317 mol) in THF (20 mL). The solution is stirred at 0° C. for 15 min,then quenched by ammonium chloride solution, and extracted with EtOAc.The organic solution is dried (Na₂SO₄), filtered, and the filtraterotary evaporated. The residue is purified by filtration through silicagel; elution with heptane and heptane:EtOAc (9:1) gives 0.70 g of theproduct 20.

Step 2

3,4-bis-(3-Fluorophenyl)-1,2,5-thiadiazole-1,1-dioxide (21)

Hydrogen chloride is bubbled through a solution of 3,3′-difluorobenzil(20) (3.81 g, 15.7 mmol) and sulfamide (1.53 g, 15.9 mmol) in methanol(15 mL) for 0.5 min followed by heating at 66° C. for 2 h. The reactionmixture is cooled to RT, the solvent rotary evaporated, and the residuetriturated from heptane to give 3.50 g of the product 21.

Step 3

cis-3,4-bis-(3-Fluorophenyl)-3-methyl-2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide(22)

To a cool (10° C.) suspension of 21 (1.50 g, 4.90 mmol) in toluene:THF(40:4 mL) is added 3.0M methylmagnesium bromide in Et₂O (2.45 mL, 7.35mmol), and the mixture is stirred at 10° C. for 0.5 h. The reactionmixture is quenched with saturated ammonium chloride, extracted withEtOAc, and the organic extract is washed with brine, dried (Na₂SO₄),filtered, and the filtrate rotary evaporated. The residue is dissolvedin methanol (15 mL), cooled to 0° C., and sodium borohydride (742 mg,20.1 mmol) is added portionwise. The mixture is stirred at 20° C. for 45min, and 5M HCl is added to bring the solution to pH 2. The mixture isextracted with EtOAc, and the organic extract is washed with brine,dried (Na₂SO₄), filtered, and the filtrate rotary evaporated to give 1.5g of the product 22.

Step 4

cis-1,2-bis-(3-Fluorophenyl)propane-1,2-diamine (23)

A suspension of 22 (1.50 g, 4.62 mmol) in 2M HBr (56 mL) containingphenol (2.17 g) is stirred and heated at reflux (130° C.) for 24 h. Themixture is cooled to RT, extracted with EtOAc, and the aqueous solutionis cooled (ice bath) and made basic (pH 14) with sodium hydroxide. Thebasic solution is extracted with EtOAc, and the extract is washed withwater, brine, then dried (Na₂SO₄), filtered, and the filtrate rotaryevaporated to give 1.06 g of the product 23.

Preparation 14 cis-4,5-Diphenylimidazolidine-2-thione (25)

A mixture of cis-1,2-diphenylethane-1,2-diamine (1) (50 g, 0.26 mol) andcarbon disulfide (24 mL, 0.40 mol) in abs. EtOH (600 mL) is heated at95° C. overnight. The reaction mixture is cooled to rt, concentrated invacuo, and the residue suspended in cold 95% EtOH, and the insolublematerial is filtered, to give 58.16 g of the product 25. ¹H NMR(DMSO-d₆) δ 8.73 (s, 2 H), 7.10-6.95 (m, 6 H), 6.95-6.85 (m, 2 H), 5.31(s, 2 H); MS: m/z 255 (M⁺+1).

Preparation 15 cis-4,5-bis-(2-Fluorophenyl)imidazolidine-2-thione (26)

A mixture of cis-1,2-bis-(2-fluorophenyl)ethane-1,2-diamine (4) (2.51 g,0.010 mol) and carbon disulfide (1.21 mL, 0.020 mol) in abs. EtOH (40mL) is heated at 90° C. for 8 h. The reaction mixture is cooled to RT,concentrated in vacuo, and the residue suspended in abs EtOH, and theinsoluble material is filtered to give 2.48 g of the product 26. ¹H NMR(CDCl₃) δ 7.20-7.05 (m, 4 H), 6.95-6.90 (m, 2 H), 6.90-6.75 (m, 2 H),6.32 (s, 2 H), 5.80 (s, 2 H); MS: m/z 291 (M⁺+1).

Preparation 16 cis-4,5-bis-(3-Fluorophenyl)imidazolidine-2-thione (27)

A mixture of cis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5) (5.0 g,0.02 mol) and carbon disulfide (2.46 mL, 0.040 mol) in abs. EtOH (50 mL)is heated at 90° C. overnight. The reaction mixture is cooled to RT,concentrated in vacuo, and the residue suspended in abs EtOH:heptane,and the insoluble material is filtered to give 4.74 g of the product 27.¹H NMR (CDCl₃) δ 7.15-7.05 (m, 2 H), 6.90-6.80 (m, 2 H), 6.80-6.70 (m,2H), 6.70-6.60 (m, 2 H), 6.33 (s, 2 H), 5.37 (s, 2 H); MS: m/z 291(M⁺+1)

Preparation 17 cis-4,5-bis-(4-Fluorophenyl)imidazolidine-2-thione (28)

A mixture of cis-1,2-bis-(4-fluorophenyl)ethane-1,2-diamine (6) (1.9 g,0.508 mol) and carbon disulfide (0.92 mL, 1.53 mol) in abs. EtOH (50 mL)is heated at 95° C. overnight. The reaction mixture is cooled to RT,concentrated in vacuo, and the residue suspended in abs EtOH, and theinsoluble material is filtered to give 1.8 g of the product 28. ¹H NMR(CDCl₃) δ 6.95-6.75 (m, 8 H), 6.54 (s, 2 H), 5.34 (s, 2 H); MS: m/z 291(M⁺+1).

Preparation 18 cis-4,5-bis-(2-Methylphenyl)imidazolidine-2-thione (29)

A mixture of cis-1,2-bis-(2-methylphenyl)ethane-1,2-diamine (11) (5.63g, 0.0234 mol) and carbon disulfide (2.82 mL, 0.0468 mol) in abs. EtOH(50 mL) is heated at 95° C. overnight. The reaction mixture is cooled toRT, concentrated in vacuo, and the residue suspended in absEtOH:heptane, and the insoluble material is filtered to give 6.10 g ofthe product 29. ¹H NMR (CDCl₃) δ 7.05-6.95 (m, 6 H), 6.95-6.90 (m, 2 H),6.11 (s, 2 H), 5.63 (s, 2 H), 2.12 (s, 3 H); MS: m/z 283 (M⁺+1).

Preparation 19 cis-4,5-bis-(3-Methylphenyl)imidazolidine-2-thione (30)

A mixture of cis-1,2-bis-(3-methylphenyl)ethane-1,2-diamine (12) (3.00g, 0.0125 mol) and carbon disulfide (1.5 mL, 0.025 mol) in abs. EtOH (30mL) is heated at 90° C. overnight. The reaction mixture is cooled to RT,concentrated in vacuo, and the residue suspended in abs EtOH, and theinsoluble material is filtered to give 2.25 g of the product 30. ¹H NMR(CDCl₃) δ 7.05-6.90 (m, 4 H), 6.85-6.80 (m, 4 H), 6.19 (s, 2 H), 5.31(s, 2 H), 2.15 (s, 6 H); MS: m/z 283 (M⁺+1).

Preparation 20 cis-4,5-bis-(4-Methylphenyl)imidazolidine-2-thione (31)(Scheme 2, Method a)

A mixture of cis-1,2-bis-(4-methylphenyl)ethane-1,2-diamine (13) (5.59g, 0.233 mol) and carbon disulfide (2.8 mL, 0.0465 mol) in abs. EtOH (30mL) is heated at 100° C. overnight. The reaction mixture is cooled toRT, concentrated in vacuo, and the residue suspended in abs.EtOH:heptane, and the insoluble material is filtered to give 5.53 g ofthe product 31. ¹H NMR (CDCl₃) δ 6.95-6.90 (d, 4 H), 6.85-6.75 (d, 4 H),6.14 (s, 2 H), 5.30 (s, 2 H), 2.21 (s, 6 H); MS: m/z 283 (M⁺+1).

Preparation 21 cis-4,5-bis-(2-Chlorophenyl)imidazolidine-2-thione (32)

A mixture of cis-1,2-bis-(2-chlorophenyl)ethane-1,2-diamine (7) (8.78 g,0.0312 mol) and carbon disulfide (3.5 mL, 0.0582 mol) in abs. EtOH (120mL) is heated at 95° C. overnight. The reaction mixture is cooled to RT,concentrated in vacuo to crystallize the product. The material isfiltered to give 10.1 g of the product 32. ¹H NMR (DMSO-d₆) δ 8.80 (s,2H), 7.25-6.95 (m, 8H0), 5.70 (s, 2H); MS: m/z 323 (M⁺+1)

Preparation 22 cis-4,5-bis-(3-Chlorophenyl)imidazolidine-2-thione (33)

A mixture of cis-1,2-bis-(3-chlorophenyl)ethane-1,2-diamine (8) (9.49 g0.0338 mol) and carbon disulfide (4.06 mL, 0.0675 mol) in abs. EtOH (150mL) is heated at 95° C. overnight. The reaction mixture is cooled to RT,concentrated in vacuo to crystallize the product. The material isfiltered to give 10.1 g of the product 33. ¹H NMR (DMSO-d₆) δ 8.85 (s,2H), 7.20-7.10 (m, 4H), 7.00-6.80 (m, 4H), 5.35 (s, 2H); MS: m/z 323(M⁺+1)

Preparation 23 cis-4,5-bis-(4-Chlorophenyl)imidazolidine-2-thione (34)

A mixture of cis-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (9) (38.1 g,0.135 mol) and carbon disulfide (16.3 mL, 0.0271 mol) in abs. EtOH (100mL) is heated at 95° C. for 6 h. The reaction mixture is cooled to RT,and the solid that formed is filtered to give 30 g of the product 34. ¹HNMR (CDCl₃) δ 7.10-7.10 (d, 4 H), 6.95-6.90 (d, 4 H), 6.43 (s, 2 H),5.33 (s, 2 H); MS: m/z 323 (M⁺+1).

Preparation 24 cis-4,5-bis-(2-Bromophenyl)imidazolidine-2-thione (35)

A mixture of the crude cis-1,2-bis-(2-bromophenyl)ethane-1,2-diamine(10) (4.07 g, 11 mmol) and carbon disulfide (2 mL, 33.3 mmol) in abs.EtOH (100 mL) is heated at 120° C. overnight. The reaction mixture iscooled to RT, and the solid that formed is filtered to give 0.56 g ofthe crude product 35.

Preparation 25 trans-(4S,5S)-Diphenylimidazolidine-2-thione (36)

A mixture of trans-(1S,2S)-(−)-diphenylethane-1,2-diamine (2) (0.5 g,2.4 mmol) and carbon disulfide (0.350 mL, 5.80 mmol) in abs. EtOH (20mL) is heated at 95° C. overnight. The reaction mixture is cooled to RT,the solvent removed by rotary evaporation, and the residue suspended incold abs. EtOH. The insoluble material is filtered to give 0.5 g of theproduct 36. ¹H NMR (DMSO-d₆) δ 8.80 (s, 2 H), 7.50-7.20 (m, 10 H), 4.66(s, 2 H); MS: m/z 255 (M⁺+1).

Preparation 26 trans-(4R,5R)-Diphenylimidazolidine-2-thione (37)

A mixture of trans-(1R,2R)-(+)-diphenylethane-1,2-diamine (3) (5.75 g,27.1 mmol) and carbon disulfide (5 mL, 81.3 mmol) in abs. EtOH (70 mL)is heated at 95° C. overnight. The reaction mixture is cooled to RT, thesolvent removed by rotary evaporation, and the residue suspended in abs.EtOH. The insoluble material is filtered to give 6.87 g of the product37. ¹H NMR (DMSO-d₆) δ 8.79 (s, 2 H), 7.50-7.20 (m, 10 H), 4.66 (s, 2H); MS: m/z 255 (M⁺+1).

Preparation 27 cis-4,5-Diphenyl-4-methylimidazolidine-2-thione (38)

A mixture of cis-1,2-diphenylpropane-1,2-diamine (16) (1.0 g, 4.42 mmol)and carbon disulfide (0.293 mL, 4.87 mmol) in abs. EtOH (5 mL) is heatedat 95° C. for 6 h. The reaction mixture is cooled to 0° C., and theprecipitate that formed is filtered to give 658 mg of the product 38. ¹HNMR (DMSO-d₆) δ 8.85 (s, 1 H), 8.65 (s, 1 H), 7.15-6.75 (m, 10 H), 4.90(s, 1 H), 1.75 (s, 3 H); MS: m/z 269 (M⁺+1).

Preparation 28cis-4,5-bis-(4-Fluorophenyl)-4-methylimidazolidine-2-thione (39)

A mixture of cis-1,2-bis-(4-fluorophenyl)propane-1,2-diamine (19) (1.24g, 4.73 mmol) and carbon disulfide (0.427 mL, 7.09 mmol) in abs. EtOH (5mL) is heated at 85° C. overnight. The reaction mixture is cooled to 0°C., and the precipitate that formed is filtered to give 1.2 g of theproduct 39.

Preparation 29cis-4,5-bis-(3-Fluorophenyl)-4-methylimidazolidine-2-thione (40)

A mixture of cis-1,2-bis-(3-fluorophenyl)propane-1,2-diamine (23) (858mg, 3.27 mmol) and carbon disulfide (0.395 mL, 6.81 mmol) in abs. MeOH(5 mL) is heated at 75° C. for 6 h. The reaction mixture is cooled toRT, the solvent evaporated, and the residue triturated with heptane. Theinsoluble material is filtered and further purified by chromatography onsilica gel; elution with heptane:EtOAc (5:1) gives 23 mg of the product40. ¹H NMR (CDCl₃) δ 7.70-7.00 (m, 2 H), 6.95-6.55 (m, 6 H), 6.47 (s, 1H), 6.23 (s, 1 H), 4.96 (s, 1 H), 1.90 (s, 3 H); MS: m/z 304 (M⁺+1).

Preparation 30 cis-1H-Benzimidazol-3a,4,5,6,7,7a-hexahydro-2-thione (41)

A mixture of cis-1,2-diaminocyclohexane (24) (10 g, 87.6 mmol) andcarbon disulfide (10.5 mL, 175 mol) in abs. EtOH (100 mL) is heated at95° C. overnight. The reaction mixture is cooled to RT, the solventevaporated, and the residue triturated with 95% EtOH. The insolublematerial is filtered to give 9.74 g of the product 41. ¹H NMR (DMSO-d₆)δ 8.08 (s, 2 H), 4.75-4.60 (m, 2 H), 1.70-1.15 (m, 8 H); MS: m/z 157(M⁺+1).

Preparation 31 cis-4,5-Diphenyl-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (42)

A mixture of cis-4,5-diphenylimidazolidine-2-thione (25) (58.16 g, 0.229mol) and methyl iodide (35.6 mL, 0.87 mol) in abs. EtOH (500 mL) isheated at 95° C. overnight. The reaction mixture is cooled to RT,concentrated in vacuo, and the residue suspended in Et₂O. The insolublematerial is filtered, washed with Et₂O to give 88.9 g of the product 42.¹H NMR (DMSO-d₆) δ 10.75 (s, 2 H), 7.25-6.95 (m, 10 H), 5.85 (s, 2 H),2.82 (s, 3H); MS: m/z 269 (M⁺+1).

Preparation 32cis-4,5-bis-(2-Fluorophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (43)

A mixture of cis-4,5-bis-(2-fluorophenyl)imidazolidine-2-thione (26)(2.45 g, 0.0084 mol) and methyl iodide (0.79 mL, 0.012 mol) in abs. EtOH(30 mL) is heated at 90° C. overnight. The reaction mixture is cooled tort, concentrated in vacuo, and the residue crystallized from absEtOH/Et₂O to give 3.42 g of the product 43. ¹H NMR (DMSO-d₆) δ 10.85 (s,2 H), 7.30-7.10 (m, 4 H), 7.10-6.90 (m, 4 H), 6.04 (s, 2 H), 2.80 (s, 3H); MS: m/z 305 (M⁺+1).

Preparation 33cis-4,5-bis-(3-Fluorophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (44)

A mixture of cis-4,5-bis-(3-fluorophenyl)imidazolidine-2-thione (27)(4.5 g, 0.0188 mol) and methyl iodide (1.45 mL, 0.0232 mol) in abs. EtOH(50 mL) is heated at 95° C. overnight. The reaction mixture is cooled toRT, concentrated in vacuo, and the residue suspended in abs EtOH/Et₂O.The insoluble material is filtered to give 6.10 g of the product 44. ¹HNMR (DMSO-d₆) δ 10.78 (s, 2 H), 7.30-7.15 (m, 2 H), 7.05-6.90 (m, 6 H);5.87 (s, 2 H), 2.87 (s, 3 H); MS: m/z 305 (M⁺+1).

Preparation 34cis-4,5-bis-(4-Fluorophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (45)

A solution of cis-4,5-bis-(4-fluorophenyl)imidazolidine-2-thione (28)(1.78 g, 0.61 mmol) and methyl iodide (0.620 g, 10.0 mmol) in abs. EtOH(30 mL) is heated at 95° C. for 26 h. The reaction mixture is cooled tort, concentrated in vacuo, and the residue suspended in abs. EtOH:Et₂O.The insoluble material is filtered to give 2.47 g of the product 45. ¹HNMR (DMSO-d₆) δ 10.75 (s, 2 H), 7.15-6.95 (m, 8 H), 5.83 (s, 2 H), 2.81(s, 3 H); MS: m/z 305 (M⁺+1).

Preparation 35cis-4,5-bis-(2-Methylphenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (46)

A mixture of cis-4,5-bis-(2-methylphenyl)imidazolidine-2-thione (29)(6.08 g, 0.0215 mol) and methyl iodide (2.01 mL, 0.0323 mol) in abs.EtOH (50 mL) is heated at 85° C. overnight. The reaction mixture iscooled to rt, concentrated in vacuo, and the residue suspended in Et₂O.The insoluble material is filtered to give 8.79 g of the product 46. ¹HNMR (DMSO-d₆) δ 10.67 (s, 2 H), 7.10-6.90 (m, 8 H), 6.02 (s, 2 H), 2.79(s, 3 H), 2.16 (s, 6 H); MS: m/z 297 (M⁺+1).

Preparation 36cis-4,5-bis-(3-Methylphenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (47)

A mixture of cis-4,5-bis-(3-methylphenyl)imidazolidine-2-thione (30)(2.23 g, 0.00825 mol) and methyl iodide (0.77 mL, 0.0124 mol) in abs.EtOH (30 mL) is heated at 95° C. overnight. The reaction mixture iscooled to rt, concentrated in vacuo, and the residue suspended in Et₂O.The insoluble material is filtered to give 3.24 g of the product 47. ¹HNMR (DMSO-d₆) δ 10.71 (s, 2 H), 7.10-7.00 (m, 2 H), 7.00-6.90 (m, 2 H),6.90-6.75 (m, 4 H), 5.73 (s, 2 H), 2.80 (s, 3 H), 2.13 (s, 6 H); MS: m/z297 (M⁺+1).

Preparation 37cis-4,5-bis-(4-Methylphenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (48)

A mixture of cis-4,5-bis-(4-methylphenyl)imidazolidine-2-thione (31)(5.2 g, 0.0184 mol) and methyl iodide (1.72 mL, 0.0276 mol) in abs. EtOH(30 mL) is heated at 90° C. overnight. The reaction mixture is cooled tort, concentrated in vacuo, and the residue suspended in abs EtOH:Et₂O.The insoluble material is filtered to give 7.56 g of the product 48. ¹HNMR (DMSO-d₆) δ 10.68 (s, 2 H), 7.00-6.85 (m, 8 H), 5.72 (s, 2 H), 2.79(s, 3 H), 2.15 (s, 6 H); MS: m/z 297 (M⁺+1).

Preparation 38cis-4,5-bis-(2-Chlorophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (49)

A mixture of cis-4,5-bis-(2-chlorophenyl)imidazolidine-2-thione (32)(10.1 g, 0.0312 mol) and methyl iodide (3.89 mL, 0.0624 mol) in abs.EtOH (15 mL) is heated at 90° C. for 6 h. The reaction mixture is cooledto rt, concentrated in vacuo, and the residue suspended in abs EtOH. Theinsoluble material is filtered to give 11 g of the product 49.

Preparation 39cis-4,5-bis-(3-Chlorophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (50)

A mixture of cis-4,5-bis-(3-chlorophenyl)imidazolidine-2-thione (33)(8.23 g, 0.0254 mol) and methyl iodide (3.17 mL, 0.0509 mol) in abs.EtOH (25 mL) is heated at 90° C. for 8 h. The reaction mixture is cooledto rt, concentrated in vacuo, and the residue triturated with abs EtOH.The insoluble material is filtered to give 10.1 g of the product 50.

Preparation 40cis-4,5-bis-(4-Chlorophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (51)

A mixture of cis-4,5-bis-(4-chlorophenyl)imidazolidine-2-thione (34) (30g, 0.0928 mol) and methyl iodide (11.5 mL, 0.186 mol) in abs. EtOH (100mL) is heated at 90° C. for 8 h. The reaction mixture is cooled to rt,concentrated in vacuo, and the residue triturated with abs EtOH. Theinsoluble material is filtered to give 32.5 g of the product 51.

Preparation 41cis-4,5-bis-(2-Bromophenyl)-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (52)

A solution of cis-4,5-bis-(2-bromophenyl)imidazolidine-2-thione (35)(0.51 g, 1.36 mmol) and methyl iodide (0.178 mL, 2.1 mmol) in abs. EtOH(20 mL) is heated at 90° C. overnight. The reaction mixture is cooled tort, concentrated in vacuo, and the residue suspended in Et₂O. Theinsoluble material is filtered to give 0.51 g of the product 52.

Preparation 42trans-(4S,5S)-Diphenyl-2-methylthio-4,5-dihydro-1H-imidazole hydroiodide(53)

A mixture of trans-(4S,5S)-diphenylimidazolidine-2-thione (36) (6.93 g,27.2 mmol) and methyl iodide (4.24 mL, 68.1 mmol) in abs. EtOH (50 mL)is heated at 95° C. overnight. The reaction mixture is cooled to rt,concentrated in vacuo, and the residue triturated with Et₂O. Theinsoluble material is filtered to give 10.5 g of the product 53. ¹H NMR(DMSO-d₆) δ 10.79 (s, 2 H), 7.55-7.35 (m, 10 H), 5.23 (s, 2 H), 2.78 (s,3 H); MS: m/z 269 (M⁺+1).

Preparation 43trans-(4R,5R)-Diphenyl-2-methylthio-4,5-dihydro-1H-imidazole hydroiodide(54)

A mixture of trans-(4R,5R)-diphenylimidazolidine-2-thione (37) (6.87 g,27.0 mmol) and methyl iodide (4 mL, 64 mmol) in abs. EtOH (50 mL) isheated at 95° C. overnight. The reaction mixture is cooled to rt,concentrated in vacuo, and the residue triturated with Et₂O. Theinsoluble material is filtered to give 9.5 g of the product 54. ¹H NMR(DMSO-d₆) δ 10.80 (d, 2 H), 7.20-6.85 (m, 10 H), 5.37 (s, 1 H), 2.79 (s,3 H), 1.92 (s, 3 H); MS: m/z 283 (M⁺+1).

Preparation 44cis-4,5-Diphenyl-4-methyl-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (55)

A mixture of cis-4,5-diphenyl-4-methylimidazolidine-2-thione (38) (655mg, 2.44 mmol) and methyl iodide (0.304 mL, 4.89 mmol) in abs. EtOH (5mL) is heated at 95° C. for 6 h. The reaction mixture is cooled to rt,concentrated in vacuo, and the residue triturated with heptane. Theinsoluble material is filtered to give 972 mg of the product 55. ¹H NMR(DMSO-d₆) δ 8.85 (s, 1 H), 8.65 (s, 1 H), 7.15-6.75 (m, 10 H), 4.90 (s,1 H), 1.75 (s, 3 H); MS: m/z 269 (M⁺+1).

Preparation 45cis-4,5-bis-4-Fluorophenyl-4-methyl-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (56)

A mixture of cis-4,5-bis-(4-fluorophenyl)-4-methylimidazolidine-2-thione(39) (1.2 g, 3.9 mmol) and methyl iodide (0.491 mL, 7.89 mmol) in abs.EtOH (5 mL) is heated to reflux for 3 h. The reaction mixture is cooledto rt, concentrated in vacuo, and the residue triturated with heptane.The insoluble material is filtered to give 1.84 g of the product 56.

Preparation 46cis-4,5-bis-1-Fluorophenyl-4-methyl-2-methylthio-4,5-dihydro-1H-imidazolehydroiodide (57)

A mixture of cis-4,5-bis-(3-Fluorophenyl)-4-methylimidazolidine-2-thione(40) (900 mg, 2.96 mmol) and methyl iodide (0.368 mL, 6.86 mmol) in abs.EtOH (4 μL) is heated at 88° C. for 6 h. The reaction mixture is cooledto rt, concentrated in vacuo, and the residue triturated with heptane.The insoluble material is filtered to give 1.3 g of the product 57.

Preparation 47 cis-3a,4,5,6,7,7a-Hexahydro-2-methylthio-1H-benzimidazolehydroiodide (58)

A mixture of cis-1H-benzimidazol-3a,4,5,6,7,7a-hexahydro-2-thione (41)(9.0 g, 57.6 mmol) and methyl iodide (5.4 mL, 86.4 mmol) in abs. EtOH(50 mL) is heated at 90° C. for 48 h. The reaction mixture is cooled tort, concentrated in vacuo, and the residue triturated with Et₂O. Theinsoluble material is filtered to give 16.77 g of the product 58. ¹H NMR(DMSO-d₆) δ 10.11 (s, 2 H), 4.25-4.10 (m, 2 H), 2.65 (s, 3 H), 1.85-1.65(m, 2H), 1.65-1.55 (m, 2 H), 1.55-1.25 (m, 4 H); MS: m/z 171 (M⁺+1).

Preparation 48cis-4,5-Diphenyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylic acid,tert-butyl ester (59)

A solution of imidazoline 42 (5.0 g, 0.0126 mol),di-tert-butyl-dicarbonate (2.75 g, 0.0126 mol), triethylamine (1.94 mL,0.0139 mol), and 4-dimethylamino-pyridine (50 mg) in dichloromethane (80mL) is stirred at rt for 3 days. The reaction mixture is extracted withwater, and the organic layer is separated, dried (MgSO₄), filtered andconcentrated in vacuo. The crude solid is purified by chromatography onsilica gel, elution with heptane:EtOAc (80:20) gives 4.3 g of theproduct 59. ¹H NMR (CDCl₃) δ 7.10-6.90 (m, 8 H), 6.90-6.75 (m, 2 H),5.57 (d, 1 H), 5.47 (d, 1 H), 2.59 (s, 3 H), 1.24 (s, 9 H); MS: m/z 369(M⁺+1).

Preparation 49cis-4,5-bis-(2-Fluorophenyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (60)

A solution of imidazoline 43 (3.3 g, 0.0076 mol),di-tert-butyl-dicarbonate (2.16 g, 0.0099 mol), triethylamine (1.28 mL,0.0092 mol), and 4-dimethylamino-pyridine (50 mg) in dichloromethane (30mL) is stirred at rt overnight. The reaction mixture is extracted withwater, and the organic layer is separated, washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The solid residue istriturated with heptane and the insoluble material filtered to give 2.57g of the product 60. ¹H NMR (CDCl₃) δ 7.30-6.65 (m, 8 H), 6.00-5.80 (m,2 H), 2.60 (s, 3 H), 1.23 (s, 9 H); MS: m/z 405 (M⁺+1).

Preparation 50cis-4,5-bis-(3-Fluorophenyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (61)

A solution of imidazoline 44 (6.0 g, 0.0139 mol),di-tert-butyl-dicarbonate (3.34 g, 0.0153 mol), triethylamine (1.81 mL,0.0167 mol), and 4-dimethylamino-pyridine (50 mg) in dichloromethane (30mL) is stirred at rt overnight. The reaction mixture is extracted withwater, and the organic layer is separated, washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(80:20-75:25), and the fractions containing the product are trituratedwith heptane and the insoluble material filtered to give 3.46 g of theproduct 61. ¹H NMR (CDCl₃) δ 7.10-6.95 (m, 2 H), 6.85-6.70 (m, 4 H),6.70-6.50 (m, 2 H), 5.57 (d, 1 H), 5.47 (d, 1 H), 2.58 (s, 3 H), 1.25(s, 9 H); MS: m/z 405 (M⁺+1).

Preparation 51cis-4,5-bis-(4-Fluorophenyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (62)

A solution of imidazoline 45 (2.45 g, 5.67 mmol), triethylamine (0.948mL, 6.8 mmol), 4-dimethylaminopyridine (50 mg), and,di-tert-butyl-dicarbonate (1.3 g, 5.9 mmol), in dichloromethane (20 mL)is stirred at rt overnight. The reaction mixture is diluted withdichloromethane, extracted with water, and the organic layer isseparated, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (75:25-50:50) gives 2.1 g of the product 62. ¹H NMR(CDCl₃) δ 6.95-6.90 (m, 2 H), 6.85-6.70 (m, 6 H), 5.55 (d, 1 H), 5.45(d, 1 H), 2.57 (s, 3 H), 1.24 (s, 9 H); MS: m/z 405 (M⁺+1).

Preparation 52cis-4,5-Di-(2-methylphenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (63)

A solution of imidazoline 46 (8.6 g, 0.0203 mol),di-tert-butyl-dicarbonate (5.31 g, 0.0243 mol), triethylamine (3.39 mL,0.0243 mol), and 4-dimethylaminopyridine (50 mg) in dichloromethane (100mL) is stirred at rt overnight. The reaction mixture is extracted withwater, and the organic layer is separated, washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue is trituratedwith heptane and the insoluble material filtered to give 7.43 g of theproduct 63. ¹H NMR (CDCl₃) δ 7.05-6.75 (m, 8 H), 5.80-5.70 (m, 2 H),2.57 (s, 3 H), 2.34 (s, 3 H), 2.04 (s, 3 H), 1.18 (s, 9 H); MS: m/z 397(M⁺+1)

Preparation 53cis-4,5-Di-(3-methylphenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (64)

A solution of imidazoline 47 (3.22 g, 0.0076 mol),di-tert-butyl-dicarbonate (1.99 g, 0.0091 mol), triethylamine (1.27 mL,0.0091 mol), and 4-dimethylaminopyridine (50 mg) in dichloromethane (30mL) is stirred at rt overnight. The reaction mixture is extracted withwater, and the organic layer is separated, washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. The residue is trituratedwith heptane and the insoluble material filtered to give 2.47 g of theproduct 64. ¹H NMR (CDCl₃) δ 6.95-6.85 (m, 2 H), 6.85-6.70 (m, 4 H),6.60-6.50 (m, 2 H), 5.50 (d, 1 H), 5.40 (d, 1 H), 2.58 (s, 3 H), 2.13(s, 6 H), 1.21 (s, 9 H); MS: m/z 397 (M⁺+1).

Preparation 54cis-4,5-Di-(4-methylphenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (65)

A solution of imidazoline 48 (7.3 g, 0.0172 mol),di-tert-butyl-dicarbonate (4.53 g, 0.0208 mol), triethylamine (2.87 mL,0.0208 mol), and 4-dimethylaminopyridine (50 mg) in dichloromethane (50mL) is stirred at rt overnight. The reaction mixture is extracted withwater, the organic layer separated, washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. The residue is suspended in heptaneand the insoluble material filtered to give 6.33 g of the product 65. ¹HNMR (CDCl₃) δ 6.90-6.80 (m, 6 H), 6.65 (d, 2 H), 5.50 (d, 1 H), 5.40 (d,1 H), 2.56 (s, 3 H), 2.17 (s, 6 H), 1.22 (s, 9 H); MS: m/z 397 (M⁺+1).

Preparation 55cis-4,5-bis-(2-Chlorophenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (66)

A cold (0° C.) solution of imidazoline 49 (11 g, 0.0237 mol),di-tert-butyl-dicarbonate (6.2 g, 0.0285 mol), N,N-diisopropylethylamine(4.95 mL, 0.00285 mol), and 4-dimethylaminopyridine (10 mg) indichloromethane (75 mL) is stirred for 10 min at 0° C., and then at rtovernight. The reaction mixture is extracted with 0.1N HCl, water, brineand dried (MgSO₄). The mixture is filtered and the filtrate concentratedin vacuo. The residue is triturated with dichloromethane:heptane and theinsoluble material filtered to give 8.2 g of the product 66.

Preparation 56cis-4,5-bis-(3-Chlorophenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (67)

A cold (0° C.) solution of imidazoline 50 (10.1 g, 0.0218 mol),di-tert-butyl-dicarbonate (5.23 g, 0.0240 mol),N,N-diisopropylethylamine (4.17 mL, 0.0240 mol), and4-dimethylaminopyridine (10 mg) in dichloromethane (200 mL) is stirredfor 10 min at 0° C., and then at rt overnight. The reaction mixture isextracted with 0.1N HCl, water, brine and then dried (MgSO₄). Themixture is filtered and the filtrate concentrated in vacuo. The residueis triturated with heptane and the insoluble material filtered to give5.19 g of the product 67.

Preparation 57cis-4,5-bis-(4-Chlorophenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (68)

A cold (0° C.) solution of imidazoline 51 (11 g, 0.0237 mol),di-tert-butyl-dicarbonate (6.2 g, 0.0285 mol), N,N-diisopropylethylamine(4.95 mL, 0.0285 mol), and 4-dimethylaminopyridine (10 mg) indichloromethane (200 mL) is stirred for 10 min at 0° C., and then at rtovernight. The reaction mixture is extracted with 0.1N HCl, water, brineand then dried (MgSO₄). The mixture is filtered and the filtrateconcentrated in vacuo. The residue is triturated with heptane and theinsoluble material filtered to give 7.95 g of the product 68.

Preparation 58cis-4,5-bis-(2-Bromophenyl)-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (69)

A solution of imidazoline 52 (0.5 g, 0.9 mmol) di-tert-butyl-dicarbonate(236 mg, 1.1 mmol), triethylamine (0.153 mL, 1.1 mmol), and4-dimethylaminopyridine (10 mg) in dichloromethane (22 mL) is stirred atrt overnight. The reaction mixture is diluted with dichloromethane,extracted with water, the organic layer separated, washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. The residue ispurified by chromatography on silica gel, eluted with heptane:EtOAc(75:25-60:40) to give 0.33 g of the product 69. ¹H NMR (CDCl₃) δ7.40-7.10 (m, 4 H), 7.00-6.85 (m, 4 H), 6.10 (d, 1 H), 6.00 (d, 1 H),2.55 (s, 3 H), 1.22 (s, 9 H); MS: m/z 525 (M++1).

Preparation 59trans-(4S,5S)-Diphenyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (70)

A solution of imidazoline 53 (10.0 g, 25.2 mmol)di-tert-butyl-dicarbonate (5.78 g, 26.5 mmol), triethylamine (3.86 mL,27.8 mmol), and 4-dimethylaminopyridine (50 mg) in dichloromethane (50mL) is stirred at rt overnight. The reaction mixture is rotaryevaporated, and the residue is dissolved in dichloromethane, andpurified by chromatography on silica gel; elution with heptane:EtOAc(50:50) to give 7.96 g of the product 70. ¹H NMR (CDCl₃) δ 7.45-7.15 (m,10 H), 4.99 (d, 1 H), 4.87 (d, 1 H), 2.57 (s, 3 H), 1.19 (s, 9 H); MS:m/z 369 (M⁺+1).

Preparation 60trans-(4R,5R)-Diphenyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (71)

A solution of imidazoline 54 (7.3 g, 18.4 mmol)di-tert-butyl-dicarbonate (4.42 g, 20.3 mmol), triethylamine (3.1 mL, 22mmol), and 4-dimethylaminopyridine (50 mg) in dichloromethane (40 mL) isstirred at rt overnight. The reaction mixture is rotary evaporated, andthe residue is dissolved in dichloromethane, and purified bychromatography on silica gel; elution with heptane:EtOAc (50:50) to give6.78 g of the product 71. ¹H NMR (CDCl₃) δ 7.45-7.15 (m, 10 H), 4.99 (d,1 H), 4.87 (d, 1 H), 2.57 (s, 3 H), 1.19 (s, 9 H); MS: m/z 369 (M⁺+1).

Preparation 61cis-4,5-Diphenyl-4-methyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (72)

A solution of imidazoline 55 (972 mg, 2.38 mmol)di-tert-butyl-dicarbonate (570 mg, 2.61 mmol), N,N-diisopropylethylamine(0.828 mL, 4.75 mmol), and 4-dimethyl-aminopyridine (10 mg) indichloromethane (15 mL) is stirred at rt for 5 h. The reaction mixtureis washed with 0.1N HCl, brine, then dried (Na₂SO₄), filtered, and thefiltrate evaporated. The residue is purified by chromatography on silicagel; elution with heptane:EtOAc (3:1) gives 850 mg of the product 72. ¹HNMR (CDCl₃) δ 7.25-7.05 (m, 2 H), 7.05-6.85 (m, 6 H), 6.85-6.70 (m, 2H), 5.05 (s, 1 H), 2.60 (s, 3 H), 1.75 (s, 3 H), 1.19 (s, 9 H); MS: m/z383 (M⁺+1).

Preparation 62cis-4,5-bis-(4-Fluorophenyl)-4-methyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (73)

A solution of imidazoline 56 (1.84 g, 3.43 mmol)di-tert-butyl-dicarbonate (899 mg, 4.12 mmol), N,N-diisopropylethylamine(1.79 mL, 10.3 mmol), and 4-dimethylaminopyridine (10 mg) indichloromethane (15 mL) is stirred at rt overnight. The reaction mixtureis washed with 0.1N HCl, brine, then dried (Na₂SO₄), filtered, and thefiltrate evaporated. The residue is purified by chromatography on silicagel; elution with heptane:EtOAc (10:1) gives 1.2 g of the product 73 and198 mg of a by-product, the correspondingtrans-4,5-bis-(4-fluorophenyl)-4-methyl isomer 74. Product 73: ¹H NMR(CDCl₃) δ 7.15-7.00 (m, 2 H), 6.95-6.60 (m, 6 H), 6.85-6.70 (m, 2 H),5.04 (s, 1 H), 2.60 (s, 3 H), 1.70 (s, 3 H), 1.20 (s, 9 H); MS: m/z 419(M⁺+1).

Preparation 63trans-4,5-bis-(4-Fluorophenyl)-4-methyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (74)

A solution of imidazoline 56 (1.84 g, 3.43 mmol)di-tert-butyl-dicarbonate (899 mg, 4.12 mmol), N,N-diisopropylethylamine(1.79 mL, 10.3 mmol), and 4-dimethyl-aminopyridine (10 mg) indichloromethane (15 mL) is stirred at rt overnight. The reaction mixtureis washed with 0.1N HCl, brine, then dried (Na₂SO₄), filtered, and thefiltrate evaporated. The residue is purified by chromatography on silicagel; elution with heptane:EtOAc (10:1) gives two products; 198 mg of theproduct 74 and 1.2 g of the cis-4,5-bis-(4-fluorophenyl)-4-methyl isomer73. Product 74: ¹H NMR (CDCl₃) δ 7.40-7.25 (m, 2 H), 7.20-7.00 (m, 6 H),5.02 (s, 1 H), 2.60 (s, 3 H), 1.15 (s, 9 H), 1.10 (s, 3 H); MS: m/z 419(M⁺+1).

Preparation 64cis-4,5-bis-(3-Fluorophenyl)-4-methyl-2-methylthio-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (75)

A solution of imidazoline 57 (1.3 g, 2.91 mmol)di-tert-butyl-dicarbonate (763 mg, 3.50 mmol), N,N-diisopropylethylamine(1.52 mL, 8.74 mmol), and 4-dimethylaminopyridine (10 mg) indichloromethane (20 mL) is stirred at rt 12 h. The reaction mixture iswashed with 0.1N HCl, sat. NaHCO₃, water, brine, and then dried(Na₂SO₄). The mixture is filtered, and the filtrate evaporated to give1.2 g of the product 75. ¹H NMR (CDCl₃) δ 7.10-6.90 (m, 2 H), 6.90-6.80(m, 2 H), 6.80-6.45 (m, 4 H), 5.03 (s, 1 H), 2.60 (s, 3 H), 1.72 (s, 3H), 1.22 (s, 9 H); MS: m/z 419 (M⁺+1).

Preparation 65cis-3a,4,5,6,7,7a-Hexahydro-2-methylthio-benzimidazole-1-carboxylicacid, tert-butyl ester (76)

A solution of imidazoline 58 (13.0 g, 43.6 mmol), triethylamine (7.9 mL,56.7 mmol), di-tert-butyl-dicarbonate (11.4 g, 52.3 mmol), and4-dimethylaminopyridine (50 mg) in dichloromethane (50 mL) is stirred atrt overnight. The reaction mixture is diluted with dichloromethane,washed with brine, dried (Mg₂SO₄), filtered. The filtrate evaporated togive 8.42 g of the product 76. ¹H NMR (CDCl₃) δ 4.15-4.05 (m, 1 H),4.00-3.90 (m, 1 H), 2.42 (s, 3 H), 2.25-1.95 (m, 2 H), 1.85-1.10 (m, 15H); MS: m/z 271 (M⁺+1).

Preparation 66 3-Phenylpropionimidic acid methyl ester hydrochloride(242)

Hydrogen chloride is bubbled into a cold (0° C.) solution of3-phenypropionitrile (5.43 g, 41.4 mmol) in methanol (2.5 mL, 62.1 mmol)for 5 min, and the mixture stirred at rt for 3 h. The solid that formedis suspended in Et₂O and filtered to give 7.8 g of the product 242. ¹HNMR (CDCl₃) δ 12.65 (s, 1 H), 11.65 (s, 1 H), 7.40-7.15 (m, 5 H), 4.24(s, 3 H), 3.08 (s, 4 H)

Preparation 67 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)amine(122)

A solution of intermediate 59 (1.0 g, 2.71 mmol) in ethylene glycol (10mL) is saturated with ammonia and is heated in a pressure tube at 115°C. for 3 h. The reaction mixture is cooled to rt, and saturated withammonia, and heated is heated at 115° C. overnight. The reaction mixtureis cooled to rt, and the product is precipitated by the addition ofaddition of water to give 226 mg of the product 122. ¹H NMR (DMSO-d₆) δ7.10-6.80 (m, 10 H), 6.40 (bs, 3 H), 5.10 (s, 2 H); LC/MS: 2.89 min, m/z238 (M⁺+1).

Preparation 68 Resolution of 1,2-diphenyl-propane-1,2-diamine

This preparative example of an intermediate illustrate the synthesis ofoptically enriched isomeric form of 1,2-diphenyl-propane-1,2-diaminethat can be employed in the syntheses of various imidazole compounds ofthe present invention following the synthetic procedures as disclosedherein.

1,2-Diphenyl-propane-1,2-diamine (7.5 grams, 0.033 mol) and(+)-di-p-toluoyl-D-tartaric acid (12.8 grams, 0.33 mol) are dissolved ina refluxing mixture of 200 mL acetonitrile and 40 mL water. The mixtureis stirred and cooled to room temperature during 3 hours. The stirringis continued for additional two hours at room temperature. Theprecipitate so formed is collected by filtration and rinsed with 90%aqueous acetonitrile, 12.1 grams of the salt is isolated with an e.e. of50% for the diamine. Recrystallization from a mixture of 170 mLacetonitrile and 35 mL water gave 8.5 g salt (chiral yield (c.y.)=42%and enantiomeric excess (e.e.) of 80% for the diamine). Anotherrecrystallization from a mixture of 170 mL acetonitrile and 35 mL watergave 6.8 g salt (c.y.=34% and e.e. of >95% for the diamine). Thecis:trans ratio is 6 to 1 based on ¹H-NMR.

Example 1 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)benzylaminehydrochloride (78)

Step 1

2-(Benzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acidtert-butyl ester (77)

A mixture of intermediate 59 (5.0 g, 0.0136 mol), benzylamine (4.5 mL,0.0407 mol) and MeOH (1 mL) is heated at 95° C. for 2 days. The reactionmixture is cooled to RT and purified by chromatography on silica gel;gradient elution with heptane:EtOAc (80:20-50:50) gives 2.81 g of theproduct 77. ¹H NMR (CDCl₃) δ 7.55-7.25 (m, 6 H), 7.10-6.85 (m, 8 H),6.85-6.70 (m, 2 H), 5.50-5.30 (m, 2 H), 4.80-4.55 (m, 2 H), 1.14 (s, 9H)

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)benzylamine hydrochloride(78)

Hydrogen chloride is bubbled into a solution of 77 (200 mg, 0.47 mmol)in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residue iscrystallized from dichloromethane and Et₂O to give 130 mg of the product78. ¹H NMR (DMSO-d₆) δ 9.80-8.30 (m, 3 H), 7.60-7.30 (m, 5 H), 7.20-7.00(m, 6 H), 7.00-6.85 (m, 4 H), 5.49 (s, 2 H), 4.59 (d, 2 H); MS: m/z 328(M⁺+1).

Example 2(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(cyclohexylmethyl)aminehydrochloride (80) (Scheme 5, Method a)

Step 1

2-(Cyclohexylmethylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (79)

A mixture of intermediate 59 (0.5 g, 1.36 mmol), cyclohexanemethylamine(0.53 mL, 6.1 mmol) and MeOH (0.11 mL) is heated at 100° C. for 48 h.The reaction mixture is cooled to RT and purified by chromatography onsilica gel; gradient elution with heptane:EtOAc (70:30-50:50) gives 0.23g of the product 79. ¹H NMR (CDCl₃) δ 7.80-7.35 (m, 2 H), 7.18 9s, 1 H),7.10-6.90 (m, 6 H), 6.90-6.70 (m, 2 H), 5.45-5.30 (m, 2 H), 3.45-3.15(m, 2 H), 2.00-1.50 (m, 5 H), 1.45-0.95 (m, 15H); MS: m/z 434 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(cyclohexylmethyl)aminehydrochloride (80)

Hydrogen chloride is bubbled into a solution of 79 (0.23 g, 0.53 mmol)in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residue trituratedwith Et₂O. The insoluble material is filtered to give 89 mg of theproduct 80. ¹H NMR (DMSO-d₆) δ 9.08 (m, 1 H), 8.54 (s, 1 H), 7.45 (m, 1H), 7.15-6.90 (m, 6 H), 6.90-6.70 (m, 4 H), 5.18 (s, 2 H), 3.35-3.10 (m,2 H), 1.90-1.65 (m, 5 H), 1.40-0.90 (m, 6 H); MS: m/z 334 (M⁺+1).

Example 3(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-N-methylbenzylaminehydrochloride (82)

Step 1

2-(N-Methylbenzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (81)

A mixture of intermediate 59 (0.4 g, 0.00109 mol), N-methylbenzylamine(0.42 mL, 0.00326 mol) and MeOH (0.1 mL) is heated at 95° C. for 2 days.The reaction mixture is cooled to RT, dichloromethane is added and themixture is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (80:20-75:25) gives 110 mg of the product 81. ¹H NMR(CDCl₃) δ 7.50-7.20 (m, 6 H), 7.10-6.90 (m, 7 H), 6.90-6.75 (m, 2 H),5.52 (q, 2 H), 4.84 (d, 1 H), 4.52 (d, 1 H), 2.97 (s, 3 H), 1.45 (s, 9H); MS: m/z 442 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-N-methylbenzylaminehydrochloride (82)

Hydrogen chloride is bubbled into a solution of 81 (110 mg, 0.25 mmol)in EtOAc (10 mL) for 1 min, and the solution is stirred at RT for 6 h.The solvent is removed by rotary evaporation, and the residue trituratedwith Et₂O. The insoluble material is dissolved in dichloromethane andEt₂O is added, and the precipitate is filtered to give 43 mg of theproduct 82. ¹H NMR (DMSO-d₆) δ 9.28 (s, 2 H), 7.60-7.30 (m, 5 H),7.25-6.95 (m, 10 H), 5.58 (s, 2 H), 4.78 (s, 2 H), 3.15 (s, 3 H); MS:m/z 342 (M⁺+1).

Example 4(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4,5-trifluorobenzyl)aminehydrochloride (84)

Step 1

cis-4,5-Diphenyl-2-(3,4,5-trifluorobenzylamino)-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (83)

A mixture of intermediate 59 (0.5 g, 1.36 mmol),3,4,5-trifluorobenzylamine (0.66 g, 4.0 mmol) and MeOH (0.2 mL) isheated at 100° C. for 2 days. The reaction mixture is cooled to RT, andthe mixture is purified by chromatography on silica gel; gradientelution with heptane:EtOAc (70:30-50:50) gives 0.44 g of the product 83.¹H NMR (CDCl₃) δ 7.59 (s, 1 H), 7.20-7.05 (m, 2 H), 7.05-6.90 (m, 8 H),6.80-6.70 (m, 2 H), 5.45-5.30 (m, 2 H), 4.70-4.50 (m, 2 H), 1.16 (s, 9H); MS: m/z 482 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4,5-trifluorobenzyl)aminehydrochloride (84)

Hydrogen chloride is bubbled into a solution of 83 (0.44 g, 0.91 mmol)in EtOAc (15 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residuecrystallized from dichloromethane and Et₂O give 0.21 g of the product84. ¹H NMR (DMSO-d₆) δ 9.40 (s, 1 H), 9.14 (t, 1 H), 7.88 (s, 1 H),7.20-6.80 (m, 8 H), 6.80-6.55 (m, 4 H), 5.07 (s, 2 H), 4.70-4.50 (m, 2H); MS: m/z 382 (M⁺+1).

Example 5(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)aminehydrochloride (86)

Step 1

2-(4-Fluorobenzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (85)

A mixture of intermediate 59 (1.0 g, 0.0027 mol), 4-fluorobenzylamine(0.372 mL, 0.00321 mol) and MeOH (0.4 mL) is heated at 100° C. for 2days. The reaction mixture is cooled to RT, and partitioned betweendichloromethane and water. The organic solution is separated, dried(MgSO₄), and concentrated in vacuo. The residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(80:20-40:60) gives 0.50 g of the product 85. ¹H NMR (CDCl₃) δ 7.60-7.35(m, 3 H), 7.15-6.90 (m, 10 H), 6.85-6.70 (m, 2 H), 5.50-5.30 (m, 2 H),5.75-5.55 (m, 2 H), 1.12 (s, 9 H); MS: m/z 446 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)aminehydrochloride (86)

Hydrogen chloride is bubbled into a solution of 85 (0.69 g, 1.58 mmol)in EtOAc (40 mL) for 2 min, and the solution is stirred at RT overnightand then at 45° C. for 3 h. The solvent is removed by rotaryevaporation, and the residue crystallized from dichloromethane and Et₂Oto give 0.52 g of the product 86. ¹H NMR (DMSO-d₆) δ 9.80-8.40 (m, 3 H),7.60-7.45 (m, 2 H), 7.35-7.25 (m, 2 H), 7.15-6.95 (m, 6 H), 6.95-6.80(m, 4 H), 5.50 (s, 2 H), 4.58 (d, 2 H); MS: m/z 346 (M⁺+1).

Example 6(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-fluorobenzyl)aminehydrochloride (88)

Step 1

2-(3-Fluorobenzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (87)

A mixture of intermediate 59 (2.0 g, 5.42 mmol), 3-fluorobenzylamine(1.86 mL, 16.2 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days.The reaction mixture is cooled to RT, and is purified twice bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-60:40) gives 1.5 g of the product 87. ¹H NMR (CDCl₃) δ 7.50 (s, 1H), 7.40-7.30 (m, 1 H), 7.30-7.15 (m, 2 H), 7.10-6.90 (m, 9 H),7.85-7.75 (m, 2 H), 5.50-5.30 (m, 2 H), 4.80-4.55 (m, 2 H), 1.15 (s, 9H); MS: m/z 446 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-fluorobenzyl)aminehydrochloride (88)

Hydrogen chloride is bubbled into a solution of 87 (1.5 g, 3.37 mmol) inEtOAc (30 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residuecrystallized from dichloromethane and Et₂O to give 1.05 g of the product88. ¹H NMR (DMSO-d₆) δ 9.28 (t, 1 H), 8.68 (s, 1 H), 8.15 (s, 1 H),7.35-7.10 (m, 3 H), 7.10-6.80 (m, 7 H), 6.80-6.50 (m, 4 H), 5.03 (s, 1H), 4.80-4.45 (m, 2 H); MS: m/z 346 (M⁺+1).

Example 7(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,5-difluorobenzyl)aminehydrochloride (90)

Step 1

2-(3,5-Difluorobenzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (89)

A mixture of intermediate 59 (0.50 g, 1.36 mmol),3,5-difluorobenzylamine (0.481 mL, 4.07 mmol) and MeOH (0.1 mL) isheated at 100° C. for 3 days. The reaction mixture is cooled to RT, andis purified by chromatography on silica gel; gradient elution withheptane:EtOAc (75:25-60:40) gives 0.28 g of the product 89. ¹H NMR(CDCl₃) δ 7.10-6.60 (m, 14 H), 5.45-5.35 (m, 2 H), 4.75-4.55 (m, 2 H),1.16 (s, 9 H); MS: m/z 464 (M⁺+1).

Step 2

cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,5-difluorobenzyl)aminehydrochloride (90))

Hydrogen chloride is bubbled into a solution of 89 (0.28 g, 0.60 mmol)in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residuecrystallized from dichloromethane and Et₂O to give 128 mg of the product90. ¹H NMR (DMSO-d₆) δ 9.31 (s, 1 H), 9.06 (t, 1 H), 7.93 (s, 1 H),7.15-6.90 (m, 9 H), 6.80-6.50 (m, 4 H), 5.02 (s, 2 H), 4.75-4.45 (m, 2H); MS: m/z 364 (M⁺+1).

Example 8(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-[2-(2-fluorophenyl)ethyl]aminehydrochloride (92)

Step 1

2-[2-(2-Fluorophenyl)ethylamino]-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (91)

A mixture of intermediate 59 (0.5 g, 1.36 mmol), 2-fluorophenethylamine(0.531 mL, 4.07 mmol) and MeOH (0.1 mL) is heated at 100° C. for 3 days.The reaction mixture is cooled to RT, and is purified by chromatographyon silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives0.27 g of the product 91. ¹H NMR (CDCl₃) δ 7.40-6.85 (m, 13 H),6.80-6.65 (m, 2 H), 5.45-5.25 (m, 2 H), 3.90-3.60 (m, 2 H), 1.15 (s, 9H); MS: m/z 460 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-[2-(2-fluorophenyl)ethyl]aminehydrochloride (92)

Hydrogen chloride is bubbled into a solution of 91 (0.37 g, 0.81 mmol)in EtOAc (10 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residuecrystallized from dichloromethane and Et₂O to give 0.21 g of the product92. ¹H NMR (DMSO-d₆) δ 9.10 (t, 1 H), 8.43 (s, 1 H), 8.58 (s, 1 H), 7.40(t, 1 H), 7.30-7.15 (m, 1 H), 7.15-6.90 (m, 8 H), 6.80-6.55 (m, 4 H),5.15 (s, 2 H), 3.80-3.45 (m, 2 H), 3.10-2.85 (m, 2 H); MS: m/z 360(M⁺+1).

Example 9(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-phenethylaminehydrochloride (94)

Step 1

2-(Phenethylamino)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole-1-carboxylicacid tert-butyl ester (93)

A mixture of intermediate 59 (2.0 g, 5.43 mmol), phenethylamine (2.04mL, 16.3 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. Thereaction mixture is cooled to RT, and is purified by chromatography onsilica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 1.06g of the product 93. ¹H NMR (CDCl₃) δ 7.40-7.30 (m, 4 H), 7.30-7.10 (m,2 H), 7.10-6.90 (m, 8 H), 6.80-6.65 (m, 2 H), 5.45-5.25 (m, 2 H),3.90-3.60 (m, 2 H), 3.05 (t, 2 H), 1.13 (s, 9 H); MS: m/z 442 (M⁺+1).

Step 2

(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-phenethylaminehydrochloride (94)

Hydrogen chloride is bubbled into a solution of 93 (1.06 g, 2.4 mmol) inEtOAc (30 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residuecrystallized from dichloromethane and Et₂O to give 0.76 g of the product94. ¹H NMR (DMSO-d₆) δ 8.95 (t, 1 H), 8.23 (s, 1 H), 7.62 (s, 1 H),7.40-7.15 (m, 6 H), 7.10-6.85 (m, 6 H), 6.80-6.45 (m, 6 H), 4.93 (s, 2H), 3.85-3.40 (m, 2 H), 3.00-2.75 (m, 2 H); MS: m/z 342 (M⁺+1).

Example 10(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-methylbenzyl)amine(95)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 3-methylbenzylamine(0.5 mL, 3.99 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 21 mg of the product 95. LC/MS: 1.76 min, m/z 342(M⁺+1).

Example 11(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4-difluorobenzyl)amine(96)

A mixture of intermediate 59 (200 mg, 0.54 mmol),3,4-difluorobenzylamine (0.5 mL, 4.23 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 72 mg of the product 96. LC/MS:1.40 min, m/z 364 (M⁺+1).

Example 12(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-chlorobenzyl)amine(97)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 3-chlorobenzylamine(0.5 mL, 4.09 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 43 mg of the product 97. LC/MS: 1.43 min, nm/z 362(M⁺+1).

Example 13(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-bromobenzyl)amine(98)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 3-bromobenzylamine(0.5 mL, 4.03 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 56 mg of the product 98. LC/MS: 1.81 min, m/z 407(M⁺+1).

Example 14(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-bromobenzyl)amine(99)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 2-bromobenzylamine(0.5 mL, 4.03 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 52 mg of the product 99. LC/MS: 1.77 min, m/z 407(M⁺+1).

Example 15(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-methylbenzyl)amine(100)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 2-methylbenzylamine(0.5 mL, 4.03 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 43 mg of the product 100. LC/MS: 1.74 min, m/z 342(M⁺+1).

Example 16(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-chloro-4-fluorobenzyl)amine(101)

A mixture of intermediate 59 (200 mg, 0.54 mmol),2-chloro-4-fluorobenzylamine (0.5 mL, 3.76 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 73 mg of the product 101. LC/MS:1.78 min, m/z 380 (M⁺+1).

Example 17(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-[2-(4-fluorophenyl)ethyl]amine(102)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 4-fluorophenethylamine(0.5 mL, 3.81 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 102 mg of the product 102. LC/MS: 1.41 min, m/z 360(M⁺+1).

Example 18(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-chlorobenzyl)amine(103)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 2-chlorobenzylamine(0.5 mL, 4.14 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 60 mg of the product 103. LC/MS: 1.37 min, m/z 362(M⁺+1).

Example 19(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-trifluoromethylbenzyl)amine(104)

A mixture of intermediate 59 (200 mg, 0.54 mmol),2-trifluoromethylbenzylamine (0.5 mL, 3.57 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 15 mg of the product 104. LC/MS:1.41 min, m/z 396 (M⁺+1).

Example 20(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2,4-dichlorobenzyl)amine(105)

A mixture of intermediate 59 (200 mg, 0.54 mmol),2,4-dichlorobenzylamine (0.5 mL, 3.74 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 110 mg of the product 105. LC/MS:1.43 min, m/z 396 (M⁺+1).

Example 21(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4-dichlorobenzyl)amine(106)

A mixture of intermediate 59 (200 mg, 0.54 mmol),3,4-dichlorobenzylamine (0.5 mL, 3.77 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 45 mg of the product 106. LC/MS:1.45 min, m/z 396 (M⁺+1).

Example 22(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2,4-difluorobenzyl)amine(107)

A mixture of intermediate 59 (200 mg, 0.54 mmol),2,4-difluorobenzylamine (0.5 mL, 4.21 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 155 mg of the product 107. LC/MS:1.37 min, m/z 364 (M⁺+1).

Example 23(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2,6-difluorobenzyl)amine(108)

A mixture of intermediate 59 (200 mg, 0.54 mmol),2,6-difluorobenzylamine (0.5 mL, 4.18 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 30 mg of the product 108. LC/MS:1.36 min, m/z 364 (M⁺+1).

Example 24(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-trifluoromethylbenzyl)amine(109)

A mixture of intermediate 59 (200 mg, 0.54 mmol),4-trifluoromethylbenzylamine (0.5 mL, 3.51 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 127 mg of the product 109. LC/MS:1.43 min, m/z 396 (M⁺+1).

Example 25(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-fluorobenzyl)amine(110)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 2-fluorobenzylamine(0.5 mL, 4.37 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 64 mg of the product 110. LC/MS: 1.36 min, m/z 346(M⁺+1).

Example 26(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-chloro-2-fluorobenzyl)amine(111)

A mixture of intermediate 59 (200 mg, 0.54 mmol),4-chloro-2-fluorobenzylamine (0.5 mL, 4.39 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 8 mg of the product 111. LC/MS:1.41 min, m/z 380 (M⁺+1).

Example 27(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-methylbenzyl)amine(112)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 4-methylbenzylamine(0.5 mL, 3.93 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 38 mg of the product 112. LC/MS: 1.75 min, m/z 342(M⁺+1).

Example 28(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-methoxybenzyl)amine(113)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 4-methoxybenzylamine(0.5 mL, 3.83 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 137 mg of the product 113. LC/MS: 1.71 min, m/z 358(M⁺+1).

Example 29(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4,5-trimethoxybenzyl)amine(114)

A mixture of intermediate 59 (200 mg, 0.54 mmol),3,4,5-trimethoxybenzylamine (0.5 mL, 2.93 mmol) is heated at 100° C.(reaction block) for 2 days. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at RT overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 111 mg of the product 114. LC/MS:1.66 min, m/z 418 (M⁺+1).

Example 30(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-chlorobenzyl)amine(115)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 4-chlorobenzylamine(0.5 mL, 4.11 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 98 mg of the product 115. LC/MS: 1.39 min, m/z 362(M⁺+1).

Example 31(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-methoxybenzyl)amine(116)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 2-methoxybenzylamine(0.5 mL, 3.83 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 37 mg of the product 116. LC/MS: 1.74 min, m/z 358(M⁺+1).

Example 32(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-methoxybenzyl)amine(117)

A mixture of intermediate 59 (200 mg, 0.54 mmol), 3-methoxybenzylamine(0.5 mL, 3.91 mmol) is heated at 100° C. (reaction block) for 2 days.The reaction mixture is cooled to RT. The corresponding N-Bocintermediate is not isolated. The reaction mixture is dissolved in EtOAc(10 mL) and hydrogen chloride is bubbled into the solution for 1 min,and the solution is stirred at RT overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 116 mg of the product 117. LC/MS: 1.70 min, m/z 358(M⁺+1).

Example 332-(4-Fluorobenzylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid phenyl ester (123)

To a solution of(cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)amine(86) (100 mg, 0.26 mmol), triethylamine (0.091 mL, 0.656 mmol),4-dimethylamino-pyridine (10 mg) in dichloromethane (10 mL) is addedphenyl chloroformate (0.033 mL, 0.262 mmol), and the mixture is stirredat RT overnight. The reaction mixture is diluted with dichloromethaneand washed with water, and the organic layer is dried (MgSO₄), filtered,and evaporated. The residue is purified by chromatography on silica gel;gradient elution with heptane:EtOAc (70:30-60:40) gives 100 mg of theproduct 123. ¹H NMR (CDCl₃) δ 7.50-7.40 (m, 2 H), 7.40-7.10 (m, 6 H),7.10-6.90 (m, 8 H), 6.90-6.80 (m, 2 H), 6.70-6.60 (m, 2 H), 5.75-5.55(m, 2 H), 4.75-4.55 (m, 2 H); MS: m/z 466 (M⁺+1)

Example 34N-[cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-4-fluorobenzamidehydrochloride (126)

Step 1

2-Amino-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acidtert-butyl ester (124)

A mixture of (cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)amine (122)(127 mg, 0.536 mmol) in dichloromethane (5 mL) is added DMF (5 mL)followed by N,N-diisopropylethylamine (0.093 mL, 0.536 mmol) and4-dimethylaminopyridine (10 mg), and the dropwise addition ofdi-tert-butyl-dicarbonate (117 mg, 0.536 mmol) in dichloromethane (2mL). The solution is stirred at RT for 1.5 h, the solvents evaporated,and the residue dissolved in dichloromethane. The solution is washedwith 0.1N HCl, NaHCO₃, water, and then dried (Na₂SO₄) and filtered. Thefiltrate is evaporated and the residue is triturated with Et₂O to give12 mg of the product 124.

Step 2

2-(4-Fluorobenzoylamino)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (125)

A mixture of 124 (200 mg, 0.593 mmol), triethylamine (0.082 mL, 0.583mmol), 4-dimethylaminopyridine (10 mg), and 4-fluorobenzoyl chloride(0.063 mL, 0.533 mmol) in dichloromethane (2 mL) is stirred at RT for0.5 h. The solution is diluted with dichloromethane and washed withNaHCO₃, brine, and then dried (MgSO₄). The mixture is filtered, thefiltrate evaporated, and residue purified by chromatography on silicagel; gradient elution with heptane:EtOAc (70:30-60:40) gives 123 mg ofthe product 125. ¹H NMR (CDCl₃) δ 10.00 (s, 1 H), 8.50-8.35 (m, 2 H),7.20-6.85 (m, 12 H), 6.55-6.40 (m, 2 H), 1.20 (s, 9 H); MS: m/z 460(M⁺+1).

Step 3

N-[cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-4-fluorobenzamidehydrochloride (126) (Scheme 5, Method c)

Hydrogen chloride is bubbled into a solution of 125 (123 mg, 0.267 mmol)in EtOAc (20 mL) for 1 min, and the solution is stirred at RT overnight.The solvent is removed by rotary evaporation, and the residue istriturated with Et₂O to give 50 mg of the product 126. ¹H NMR (DMSO-d₆)δ 12.9 (s, 1 H), 9.70 (s, 2 H), 8.35-8.15 (m, 2 H), 7.60-7.40 (m, 2 H),7.20-6.90 (m, 10), 5.70 (s, 2 H); LC/MS: 3.20 m/z 360 (M⁺+1).

Example 35(cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl)-benzylaminehydrochloride (127)

A mixture of intermediate 60 (300 mg, 0.742 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 67 mg of the product127. LC/MS: 1.43 min, m/z 364 (M⁺+1).

Example 36(cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)aminehydrochloride (128)

A mixture of intermediate 60 (300 mg, 0.742 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 107 mg of the product128. LC/MS: 1.44 min, m/z 382 (M⁺+1).

Example 37[cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (129)

A mixture of intermediate 60 (300 mg, 0.742 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 188 mg of the product 129. LC/MS: 1.45 min, m/z 400 (M⁺+1).

Example 38[cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-methylbenzyl)aminehydrochloride (130)

A mixture of intermediate 60 (300 mg, 0.742 mmol), 3-methylbenzylamine(0.5 mL, 3.9 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 80 mg of the product130. LC/MS: 1.44 min, m/z 382 (M⁺+1).

Example 39[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (131)

A mixture of intermediate 61 (300 mg, 0.742 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 110 mg of the product131. LC/MS: 1.43 min, m/z 364 (M⁺+1).

Example 40[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (132)

A mixture of intermediate 61 (300 mg, 0.742 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 108 mg of the product132. LC/MS: 1.45 min, m/z 382 (M⁺+1).

Example 41[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (133)

A mixture of intermediate 61 (300 mg, 0.742 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 160 mg of the product133. LC/MS: 1.44 min, m/z 382 (M⁺+1).

Example 42[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (134)

A mixture of intermediate 61 (300 mg, 0.742 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 210 mg of the product 134. LC/MS: 1.46 min, m/z 400 (M⁺+1).

Example 43[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (135)

A mixture of intermediate 63 (300 mg, 0.760 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 150 mg of the product135. LC/MS: 1.48 min, m/z 356 (M⁺+1).

Example 44[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (136)

A mixture of intermediate 63 (300 mg, 0.760 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 178 mg of the product136. LC/MS: 1.49 min, m/z 374 (M⁺+1).

Example 45[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (137)

A mixture of intermediate 63 (300 mg, 0.760 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 143 mg of the product137. LC/MS: 1.48 min, m/z 374 (M⁺+1).

Example 46[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (138)

A mixture of intermediate 63 (300 mg, 0.760 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 77 mg of the product 138. LC/MS: 1.49 min, m/z 392 (M⁺+1).

Example 47[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (139)

A mixture of intermediate 64 (300 mg, 0.760 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 133 mg of the product139. LC/MS: 1.49 min, m/z 356 (M⁺+1).

Example 48[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (140)

A mixture of intermediate 64 (300 mg, 0.760 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 160 mg of the product140. LC/MS: 1.50 min, m/z 374 (M⁺+1).

Example 49[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (141)

A mixture of intermediate 64 (300 mg, 0.760 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 172 mg of the product141. LC/MS: 1.50 min, m/z 374 (M⁺+1).

Example 50[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (142)

A mixture of intermediate 64 (300 mg, 0.760 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 174 mg of the product 142. LC/MS: 1.52 min, m/z 392 (M⁺+1).

Example 51[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (143) (Scheme 5, Method a)

A mixture of intermediate 65 (300 mg, 0.760 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 135 mg of the product143. LC/MS: 1.48 min, m/z 356 (M⁺+1).

Example 52[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (144)

A mixture of intermediate 65 (300 mg, 0.760 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 95 mg of the product144. LC/MS: 1.50 min, m/z 374 (M⁺+1).

Example 53[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (145)

A mixture of intermediate 65 (300 mg, 0.760 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 110 mg of the product145. LC/MS: 1.51 min, m/z 374 (M⁺+1).

Example 54[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (146)

A mixture of intermediate 65 (300 mg, 0.760 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 130 mg of the product 146. LC/MS: 1.51 min, m/z 392 (M⁺+1).

Example 55[cis-4,5-bis-(3-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (147)

A mixture of intermediate 67 (300 mg, 0.690 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 168 mg of the product147. LC/MS: 1.51 min, nm/z 396 (M⁺+1).

Example 56[cis-4,5-bis-(3-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (148)

A mixture of intermediate 67 (300 mg, 0.690 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 195 mg of the product148. LC/MS: 1.51 min, m/z 414 (M⁺+1).

Example 57[cis-4,5-bis-(3-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (149)

A mixture of intermediate 67 (300 mg, 0.690 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 135 mg of the product 149. LC/MS: 1.52 min, m/z 432 (M⁺+1).

Example 58[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (150)

A mixture of intermediate 66 (300 mg, 0.69 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 170 mg of the product150. LC/MS: 1.47 min, m/z 396 (M⁺+1).

Example 59[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (151)

A mixture of intermediate 66 (300 mg, 0.69 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 216 mg of the product151. LC/MS: 1.49 min, m/z 414 (M⁺+1).

Example 60[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (152)

A mixture of intermediate 66 (300 mg, 0.69 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 216 mg of the product152. LC/MS: 1.49 min, m/z 414 (M⁺+1).

Example 61[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (153)

A mixture of intermediate 66 (300 mg, 0.69 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 100 mg of the product 153. LC/MS: 1.50 min, m/z 432 (M⁺+1).

Example 62[cis-4,5-bis-(4-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (154)

A mixture of intermediate 68 (300 mg, 0.690 mmol), benzylamine (0.5 mL,4.6 mmol) is heated at 95° C. (reaction block) overnight. The reactionmixture is cooled to RT. The corresponding N-Boc intermediate is notisolated. The reaction mixture is dissolved in dichloromethane, washedwith 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 170 mg of the product154. LC/MS: 1.49 min, m/z 396 (M⁺+1).

Example 63[cis-4,5-bis-(4-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (155)

A mixture of intermediate 68 (300 mg, 0.690 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 216 mg of the product155. LC/MS: 1.52 min, m/z 414 (M⁺+1).

Example 64[cis-4,5-bis-(4-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (156)

A mixture of intermediate 68 (300 mg, 0.690 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 95° C. (reactionblock) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in dichloromethane, washed with 0.1N HCl, H₂O, brine, andthen dried (MgSO₄). The mixture is filtered and evaporated, and theresidue dissolved in EtOAc. Hydrogen chloride is bubbled into thesolution for 5 min, and the solution is stirred at RT overnight. Thesolvent is evaporated, and the residue is purified by chromatography onsilica gel; elution with dichloromethane:MeOH:acetic acid (100:4:1)gives 100 mg of the product 156. LC/MS: 1.54 min, m/z 432 (M⁺+1).

Example 65[cis-4,5-bis-(2-Bromophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3-fluorobenzyl)aminehydrochloride (157)

A mixture of intermediate 69 (80 mg, 015 mmol), 3-fluorobenzylamine (0.5mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 46 mg of the product157. LC/MS: 1.49 min, m/z 504 (M⁺+1).

Example 66[cis-4,5-bis-(2-Bromophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (158)

A mixture of intermediate 69 (80 mg, 015 mmol), 4-fluorobenzylamine (0.5mL, 4.4 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 33 mg of the product158. LC/MS: 1.49 min, m/z 504 (M⁺+1).

Example 67[cis-4,5-bis-(2-Bromophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (159)

A mixture of intermediate 69 (80 mg, 015 mmol), 3,4-difluorobenzylamine(0.5 mL, 4.2 mmol) is heated at 95° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in dichloromethane,washed with 0.1N HCl, H₂O, brine, and then dried (MgSO₄). The mixture isfiltered and evaporated, and the residue dissolved in EtOAc. Hydrogenchloride is bubbled into the solution for 5 min, and the solution isstirred at RT overnight. The solvent is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:acetic acid (100:4:1) gives 58 mg of the product159. LC/MS: 1.53 min, m/z 522 (M⁺+1).

Example 68[cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (161)

Step 1

2-(Benzylamino)-cis-4,5-bis-(4-fluorophenyl)-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (160)

A mixture of intermediate 62 (0.5 g, 1.24 mmol), benzylamine (0.680 mL,6.2 mmol) and MeOH (0.1 mL) is heated at 100° C. overnight. The reactionmixture is cooled to RT and purified by chromatography on silica gel;gradient elution with heptane:EtOAc (75:25-60:40) gives 0.354 g of theproduct 160. ¹H NMR (CDCl₃) δ 7.55-7.25 (m, 6 H), 6.95-6.85 (m, 2 H),6.80-6.60 (m, 6 H), 5.45-5.20 (m, 2 H), 4.75-4.55 (m, 2 H), 1.16 (s, 9H)

Step 2

[cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-benzylaminehydrochloride (161)

Hydrogen chloride is bubbled into a solution of 160 (350 mg, 0.76 mmol)in EtOAc (20 mL) for 0.5 min, and the solution is stirred at RTovernight. The solvent is removed by rotary evaporation, and the residueis triturated with Et₂O to give 230 mg of the product 161. ¹H NMR(DMSO-d₆) δ 9.50-8.40 (m, 3 H), 7.55-7.250 (m, 5 H), 7.05-6.85 (m, 8 H),5.48 (s, 2 H), 4.55 (d, 2 H); MS: m/z 364 (M⁺+1).

Example 69cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)aminehydrochloride (163)

Step 1

2-(4-Fluorobenzyamino)-cis-4,5-bis-(4-fluorophenyl)-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (162)

A mixture of intermediate 62 (0.5 g, 1.24 mmol), 4-fluorobenzylamine(0.71 mL, 6.2 mmol) and MeOH (0.2 mL) is heated at 110° C. overnight.The reaction mixture is cooled to RT diluted with dichloromethane (3mL), and purified by chromatography on silica gel; gradient elution withheptane:EtOAc (70:30-50:50) gives 0.326 g of the product 162. ¹H NMR(CDCl₃) δ 7.55-7.35 (m, 2 H), 7.10-7.00 (m, 2 H), 6.95-6.85 (m, 2 H),6.80-6.65 (m, 6 H), 5.45-5.25 (m, 2 H), 4.75-4.55 (m, 2 H), 1.16 (s, 9H).

Step 2

cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)-aminehydrochloride (163)

Hydrogen chloride is bubbled into a solution of intermediate 162 (320mg, 0.66 mmol) in EtOAc (20 mL) for 0.5 min, and the solution is stirredat RT overnight. The solvent is removed by rotary evaporation, and theresidue is crystallized from dichloromethane:Et₂O to give 89 mg of theproduct 163. ¹H NMR (DMSO-d₆) δ 9.80-8.20 (m, 3 H), 7.60-7.40 (m, 2 H),7.35-7.20 (m, 2 H), 5.50 (s, 2 H), 4.58 (s, 2 H); MS: m/z 382 (M⁺+1).

Example 70cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (165)

Step 1

2-(3,4-Difluorobenzyamino)-cis-4,5-bis-(4-fluorophenyl)-4,5-dihydro-imidazole-1-carboxylicacid tert-butyl ester (164)

A mixture of intermediate 62 (0.5 g, 1.24 mmol), 3,4-difluorobenzylamine(0.731 mL, 6.20 mmol) and MeOH (0.1 mL) is heated at 100° C. overnight.The reaction mixture is cooled to RT, and purified by chromatography onsilica gel; gradient elution with heptane:EtOAc (75:25-50:50) gives0.348 g of the product 164. ¹H NMR (CDCl₃) δ 7.52 (s, 1 H), 7.35-7.25(m, 1 H), 7.20-7.10 (m, 2 H), 6.90-6.85 (m, 2 H), 6.80-6.85 (m, 6 H),5.45-5.30 (m, 2 H), 4.70-4.50 (m, 2 H), 1.17 (s, 9 H).

Step 2

cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4-difluorobenzyl)-aminehydrochloride (165)

Hydrogen chloride is bubbled into a solution of 164 (348 mg, 0.67 mmol)in EtOAc (20 mL) for 0.5 min, and the solution is stirred at RTovernight. The solvent is removed by rotary evaporation, and the residueis triturated with Et₂O to give 199 mg of the product 165. ¹H NMR(DMSO-d₆) δ 9.70-8.40 (m, 3 H), 7.65-7.20 (m, 3 H), 7.10-6.80 (m, 8 H),5.51 (s, 2 H), 4.60 (d, 2 H); MS: m/z 400 (M⁺+1).

Example 71(cis-4,5-Diphenyl-4-methyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)aminehydrochloride (185)

A mixture of intermediate 72 (850 mg, 2.22 mmol), 4-fluorobenzylamine (1mL, 8.35 mmol) is heated at 140° C. overnight. The reaction mixture iscooled to RT. The reaction mixture is diluted with dichloromethane,washed with 0.1N HCl, brine, and then dried (Na₂SO₄). The mixture isfiltered, the filtrate evaporated, and the residue crystallized fromdichloromethane:heptane gives 365 mg of the product 185. ¹H NMR(DMSO-d₆) δ 9.80-8.40 (m, 3 H), 7.65-7.45 (m, 2 H), 7.40-7.30 (m, 2 H),7.15-6.95 (m, 6H), 6.95-6.75 (m, 4 H), 5.10 (s, 1 H), 4.70-4.50 (m, 2H), 1.85 (s, 3 H); MS: m/z 360 (M⁺+1).

Example 72[4,5-cis-bis-(4-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-(4-fluoro-benzyl)amine(186)

A mixture of intermediate 73 (200 mg, 0.478 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 145° C. overnight. The reaction mixtureis cooled to RT. The reaction mixture is diluted with dichloromethane,washed with 3M HCl, brine, and then dried (Na₂SO₄). The mixture isfiltered, the filtrate evaporated, and the residue triturated withdichloromethane, and the insoluble material filtered to give 133 mg ofthe product 186. ¹H NMR (DMSO-d₆) δ 9.80-8.40 (m, 3 H), 7.60-7.40 (m, 2H), 7.40-7.20 (m, 2 H), 7.15-6.80 (m, 8H), 5.10 (s, 1 H), 4.70-4.40 (m,2 H), 1.85 (s, 3 H); MS: m/z 396 (M⁺+1).

Example 73cis-4,5-bis-(3-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-(4-fluoro-benzyl)amine(188)

A mixture of intermediate 75 (200 mg, 0.478 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 150° C. overnight. The reaction mixtureis cooled to RT. The reaction mixture is diluted with dichloromethane,washed with 3M HCl, brine, and then dried (Na₂SO₄). The mixture isfiltered, the filtrate evaporated, and the residue purified bychromatography on silica gel; gradient elution withdichloromethane:MeOH:HOAc (100:2:0.5-100:4:1) gives 90 mg of the product188. ¹H NMR (CDCl₃) δ 9.80-7.60 (m, 2 H), 7.60-7.30 (m, 2 H), 7.15-6.85(m, 4 H), 6.85-6.70 (m, 2 H), 6.70-6.20 (m, 4 H), 4.75 (s, 1 H),4.70-4.40 (m, 2 H), 1.90 (s, 3 H); MS: m/z 396 (M⁺+1).

Example 74(cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-benzylaminehydrochloride (190)

Step 1

2-(Benzylamino)-cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-1-carboxylicacid tert-butyl ester (189)

A mixture of intermediate 76 (200 mg, 0.0.740 mmol), benzylamine (0.5mL, 4.6 mmol) is heated at 100° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The reaction mixture is diluted withdichloromethane, washed with 0.1N HCl, and brine. The solvent isevaporated, and the residue triturated with EtOAc, and the insolublematerial filtered to give 207 mg of the product 189. ¹H NMR (CDCl₃) δ8.56 (s, 1 H), 7.50-7.20 (m, 5 H), 5.15-4.95 (m, 2 H), 4.35-4.05 (m, 2H), 2.85-2.55 (m, 1 H), 2.25-2.05 (m, 1 H), 1.90-1.05 (m, 15 H); MS: m/z330 (M⁺+1).

Step 2

cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-benzylaminehydrochloride (190)

A solution of intermediate 189 (150 mg, 0.455 mmol) in EtOAc (5 mL) issaturated with hydrogen chloride for 3 min, and stirred at RT overnight.The solvent is evaporated, and the residue is triturated withdichloromethane and the insoluble material filtered to give 35 mg of theproduct 190. ¹H NMR (CDCl₃) δ 8.62 (s, 1 H), 8.40 (s, 1 H), 7.70 (s,1H), 7.45-7.05 (m, 5 H), 4.50 (s, 2 H), 3.75 (s, 2 H), 2.00-1.00 (m, 8H); MS: m/z 230 (M⁺+1).

Example 75cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-(3-fluorobenzyl)aminehydrochloride (192)

Step 1

2-[(3-Fluorobenzyl)amino]-cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-1-carboxylicacid tert-butyl ester (191)

A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 3-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The reaction mixture is diluted withdichloromethane, washed with 0.1N HCl, and brine. The solvent isevaporated, and the residue triturated with EtOAc, and the insolublematerial filtered to give 188 mg of the product 191. ¹H NMR (CDCl₃) δ8.56 (s, 1 H), 7.45-7.20 (m, 3 H), 7.20-6.95 (m, 2 H), 5.20-4.95 (m, 2H), 4.35-4.10 (m, 2 H), 2.75-2.55 (m, 1 H), 2.20-2.05 (m, 1 H),1.80-1.05 (m, 15 H); MS: m/z 348 (M⁺+1).

Step 2

cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-(3-fluorobenzyl)aminehydrochloride (192)

A solution of 191 (150 mg, 0.432 mmol) in EtOAc (5 mL) is saturated withhydrogen chloride for 3 min, and stirred at RT overnight. The solvent isevaporated, and the residue is triturated with dichloromethane and theinsoluble material filtered to give 90 mg of the product 192. ¹H NMR(CDCl₃) δ 8.80 (s, 1 H), 8.65 (s, 1 H), 7.55 (s, 1 H), 7.25-6.75 (m, 4H), 4.55 (s, 2 H), 3.80 (s, 2 H), 2.00-1.05 (m, 8 H); MS: m/z 248(M⁺+1).

Example 76cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-(4-fluorobenzyl)aminehydrochloride (194)

Step 1

2-[(4-Fluorobenzyl)amino]-cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-1-carboxylicacid tert-butyl ester (193)

A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 4-fluorobenzylamine(0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. Thereaction mixture is cooled to RT. The reaction mixture is diluted withdichloromethane, washed with 0.1N HCl, and brine. The solvent isevaporated, and the residue triturated with EtOAc, and the insolublematerial filtered to give 252 mg of the product 193. ¹H NMR (CDCl₃) δ8.55 (s, 1 H), 7.55-7.35 (m, 2 H), 7.10-7.00 (m, 2 H), 5.10-4.90 (m, 2H), 4.30-4.10 (m, 2 H), 2.70-2.55 (m, 1 H), 2.20-2.05 (m, 1 H),1.80-1.05 (m, 15 H); MS: m/z 348 (M⁺+1)

Step 2

cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-(3-fluorobenzyl)aminehydrochloride (194)

A solution of 193 (150 mg, 0.432 mmol) in EtOAc (5 mL) is saturated withhydrogen chloride for 3 min, and stirred at RT overnight. The solvent isevaporated, and the residue is triturated with dichloromethane and theinsoluble material filtered to give 30 mg of the product 194. ¹H NMR(CDCl₃) δ 9.20-7.40 (m, 3 H), 7.40-7.15 (m, 2 H), 7.05-6.85 (m, 2 H),4.50 (s, 2 H), 3.80 (s, 2 H), 1.90-1.15 (m, 8 H); MS: m/z 248 (M⁺+1).

Example 77cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-(3,4-difluorobenzyl)aminehydrochloride (196)

Step 1

2-[(3,4-Difluorobenzyl)amino]-cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-1-carboxylicacid tert-butyl ester (195)

A mixture of intermediate 76 (200 mg, 0.740 mmol),3,4-difluorobenzylamine (0.5 mL, 4.2 mmol) is heated at 100° C.(reaction block) overnight. The reaction mixture is cooled to RT. Thereaction mixture is diluted with dichloromethane, washed with 0.1N HCl,and brine. The solvent is evaporated, and the residue triturated withEtOAc, and the insoluble material filtered to give 270 mg of the product195. ¹H NMR (CDCl₃) δ 8.60 (s, 1 H), 7.40-7.10 (m, 3 H), 5.15-4.90 (m, 2H), 4.30-4.10 (m, 2 H), 2.70-2.55 (m, 1 H), 2.20-2.05 (m, 1 H),1.85-1.10 (m, 15 H); MS: m/z 366 (M⁺+1).

Step 2

cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl)-(3,4-difluorobenzyl)aminehydrochloride (196)

A solution of intermediate 195 (150 mg, 0.410 mmol) in EtOAc (5 mL) issaturated with hydrogen chloride for 3 min, and stirred at RT overnight.The solvent is evaporated, and the residue is triturated withdichloromethane and the insoluble material filtered to give 35 mg of theproduct 196. ¹H NMR (CDCl₃) δ 8.80 (s, 2 H), 7.50 (s, 1 H), 7.40-6.90(m, 3 H), 4.55 (s, 2 H), 3.80 (s, 2 H), 2.00-1.10 (m, 8 H); MS: m/z 266(M⁺+1).

Example 782-[(4-Fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (197)

A mixture of intermediate 25 (0.50 g, 1.9 mmol) and 4-fluorobenzylchloride (0.47 mL, 0.3.93 mmol) in abs. EtOH (20 mL) is heated at 90° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 0.70 g of the product 197. ¹H NMR (DMSO-d₆) δ 11.37 (s, 2H),7.75-7.65 (m, 2 H), 7.40-7.25 (m, 2 H), 7.15-6.95 (m, 6 H), 6.90-6.70(m, 4 H), 5.78 (s, 2 H), 4.84 (s, 2 H); MS: m/z 363 (M⁺+1).

Example 79[4-tert-Butylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (198)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-tert-butylbenzylchloride (0.304 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 112 mg of the product 198. ¹H NMR (DMSO-d₆) δ 11.20 (s, 2 H),7.60-7.40 (m, 4 H), 7.15-6.90 (m, 6 H), 6.90-6.70 (m, 4 H), 5.78 (s, 2H), 4.75 (s, 2 H), 1.35 (s, 9 H); MS: m/z 401 (M⁺+1).

Example 802-[(2,4-Dichlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (199)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,4-dichlorobenzylchloride (0.218 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 287 mg of the product 199. ¹H NMR (DMSO-d₆) δ 11.38 (s, 2 H),7.95-7.75 (m, 2 H), 7.65-7.50 (m, 1 H), 7.20-7.00 (m, 6 H), 7.00-6.80(m, 4 H), 5.83 (s, 2 H), 4.90 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 812-[(4-Chlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (200)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-chlorobenzylchloride (0.253 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 151 mg of the product 200. ¹H NMR (DMSO-d₆) δ 11.30 (s, 2 H),7.75-7.60 (d, 2 H), 7.60-7.55 (d, 2 H), 7.20-6.90 (m, 6 H), 6.85-6.65(m, 4 H), 5.78 (s, 2 H), 4.90 (s, 2 H); MS: m/z 379 (M⁺+1).

Example 82 2-(Benzylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (201)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and benzyl chloride(0.184 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h.The reaction mixture is cooled to RT, evaporated to dryness, and theresidue suspended in Et₂O. The insoluble material is filtered to give128 mg of the product 201. ¹H NMR (DMSO-d₆) δ 11.30 (s, 2H), 7.70-7.50(m, 2 H), 7.50-7.35 (m, 3 H), 7.20-6.95 (m, 6 H), 6.90-6.70 (m, 4 H),5.78 (s, 2H), 4.90 (s, 2 H); MS: m/z 345 (M⁺+1).

Example 832-[(3-Trifluoromethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (202)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and3-trifluoromethylbenzyl chloride (0.243 mL, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 196 mg of the product 202. ¹H NMR (DMSO-d₆)δ 11.32 (s, 2 H), 8.10-7.65 (m, 4 H), 7.15-6.95 (m, 6 H), 6.90-6.60 (m,4 H), 5.78 (s, 2 H), 4.93 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 842-[(3-Chlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (203)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-chlorobenzylchloride (0.199 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 196 mg of the product 203. ¹H NMR (DMSO-d₆) δ 11.37 (s, 2 H),7.85-7.45 (m, 4 H), 7.20-6.90 (m, 6 H), 6.90-6.60 (m, 4 H), 5.78 (s, 2H), 4.93 (s, 2 H); MS: m/z 379 (M⁺+1).

Example 852-[(3,4-Dichlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (204)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,4-dichlorobenzylchloride (0.218 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 217 mg of the product 204. ¹H NMR (DMSO-d₆) δ 11.40 (s, 2 H), 7.95(d, 1 H), 7.78 (d, 1 H), 7.65 (d, 1 H), 7.20-6.90 (m, 6 H), 6.90-6.60(m, 4 H), 5.78 (s, 2 H), 4.85 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 864-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)thiomethyl]benzoicacid ethyl ester hydrochloride (205)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and4-chloromethylbenzoic acid ethyl ester (0.268 mg, 1.57 mmol) in abs.EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooledto RT, evaporated to dryness, and the residue suspended in Et₂O. Theinsoluble material is filtered to give 278 mg of the product 205. ¹H NMR(DMSO-d₆) δ 11.20 (s, 2 H), 8.00 (d, 2 H), 7.75 (d, 2 H), 7.15-6.90 (m,6 H), 6.90-6.65 (m, 4 H), 5.78 (s, 2 H), 4.90 (s, 2 H), 4.35 (q, 2 H),1.32 (t, 3 H); MS: m/z 417 (M⁺+1).

Example 872-[(3,5-Dimethoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (206)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and3,5-dimethoxybenzyl chloride (0.293 mg, 1.57 mmol) in abs. EtOH (2 mL)is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 189 mg of the product 206. ¹H NMR (DMSO-d₆)δ 11.37 (s, 2 H), 7.85-7.45 (m, 4 H), 7.20-6.90 (m, 6 H), 6.90-6.60 (m,4 H), 5.78 (s, 2 H), 4.70 (s, 2 H), 3.78 (s, 6 H); MS: m/z 405 (M⁺+1).

Example 882-[(4-Phenylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (207)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-phenylbenzylchloride (0.318 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 205 mg of the product 207. ¹H NMR (DMSO-d₆) δ 11.24 (s, 2 H),7.90-7.60 (m, 6 H), 7.60-7.30 (m, 3 H), 7.20-6.90 (m, 6 H), 6.90-6.65(m, 4 H), 5.79 (s, 2 H), 4.85 (s, 2 H); MS: m/z 421 (M⁺+1).

Example 892-[(2-Chlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (208)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-chlorobenzylchloride (0.198 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 105 mg of the product 208. ¹H NMR (DMSO-d₆) δ 11.38 (s, 2 H),7.90-7.70 (m, 1 H), 7.70-7.55 (m, 1 H), 7.55-7.35 (m, 2 H), 7.20-7.00(m, 6 H), 7.00-6.85 (m, 4 H), 5.81 (s, 2 H), 4.88 (s, 2 H); MS: m/z 379(M++1).

Example 902-[(2,6-Dichlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (209)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,6-dichlorobenzylchloride (0.307 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 296 mg of the product 209. ¹H NMR (DMSO-d₆) δ 11.47 (s, 2 H),7.75-7.60 (m, 2 H), 7.60-7.40 (m, 1 H), 7.30-6.85 (m, 10 H), 5.90 (s, 2H), 4.98 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 912-[(2-Fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (210)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-fluorobenzylchloride (0.187 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 141 mg of the product 210. ¹H NMR (DMSO-d₆) δ 11.28 (s, 2 H),7.80-7.65 (m, 1 H), 7.60-7.40 (m, 1 H), 7.40-7.20 (m, 2 H), 7.20-7.00(m, 6 H), 7.00-6.80 (m, 4 H), 5.80 (s, 2 H), 4.85 (s, 2 H); MS: m/z 363(M⁺+1).

Example 922-[(4-Methylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (211)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-methylbenzylchloride (0.208 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 199 mg of the product 211. ¹H NMR (DMSO-d₆) δ 11.18 (s, 2 H), 7.45(d, 2 H), 7.25 (d, 2 H), 7.20-6.90 (m, 6 H), 6.90-6.65 (m, 4 H), 5.77(s, 2 H), 4.73 (s, 2 H), 2.35 (s, 3 H); MS: m/z 359 (M++1).

Example 932-[(3-Methylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (212)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-methylbenzylchloride (0.207 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 180 mg of the product 212. ¹H NMR (DMSO-d₆) δ 11.21 (s, 2 H),7.50-7.20 (m, 4 H), 7.20-6.90 (m, 6 H), 6.90-6.65 (m, 4 H), 5.73 (s, 2H), 4.75 (s, 2 H), 2.32 (s, 3 H); MS: m/z 359 (M⁺+1).

Example 942-[(Naphthalen-1-yl)methylthio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (213)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and1-chloromethylnaphthalene (0.277 mg, 1.57 mmol) in abs. EtOH (2 mL) isheated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 67 mg of the product 213. ¹H NMR (DMSO-d₆)δ 11.20 (s, 2 H), 8.40-8.25 (m, 1 H), 8.10-7.90 (m, 2 H), 7.90-7.80 (m,1 H), 7.80-7.50 (3, H), 7.20-6.70 (m, 10 H), 5.79 (s, 2 H), 4.85 (s, 2H); MS: m/z 395 (M⁺+1).

Example 952-[(3,4-Difluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (214)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,4-difluorobenzylchloride (0.255 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 207 mg of the product 214. ¹H NMR (DMSO-d₆) δ 11.38 (s, 2 H),7.90-7.65 (m, 1 H), 7.65-7.40 (m, 2 H), 7.20-6.90 (m, 6 H), 6.90-6.65(m, 4 H), 5.79 (s, 2 H), 4.85 (s, 2 H); MS: m/z 381 (M⁺+1).

Example 962-[(2-Trifluoromethoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (215)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and2-trifluoromethoxybenzyl chloride (0.331 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 202 mg of the product 215. ¹H NMR (DMSO-d₆)δ 11.32 (s, 2 H), 7.85 (d, 1 H), 7.70-7.40 (m, 3 H), 7.20-6.70 (m, 10H), 5.80 (s, 2 H), 4.85 (s, 2 H); MS: m/z 429 (M⁺+1).

Example 972-[(4-Trifluoromethoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (216)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and4-trifluoromethoxybenzyl chloride (0.331 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 229 mg of the product 216. ¹H NMR (DMSO-d₆)δ 11.30 (s, 2 H), 7.75 (d, 2 H), 7.45 (d, 2 H), 7.20-6.90 (m, 6 H),6.90-6.60 (m, 4 H), 5.79 (s, 2 H), 4.85 (s, 2 H); MS: m/z 429 (M⁺+1).

Example 982-[(3,4,5-Trimethoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (217)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and3,4,5-trimethoxybenzyl chloride (0.340 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 93 mg of the product 217. ¹H NMR (DMSO-d₆)δ 11.10 (m, 2 H), 7.25-6.90 (m, 8 H), 6.90-6.70 (m, 4 H), 5.80 (d, 2 H),4.70 (s, 1 H), 3.78 (s, 6 H), 3.70 (s, 1 H)

Example 992-[(3-Methoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (218)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-methoxybenzylchloride (0.288 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 212 mg of the product 218. ¹H NMR (DMSO-d₆) δ 11.26 (s, 2 H), 7.40(t, 1 H), 7.30-7.10 (m, 2 H), 7.10-6.90 (m, 7 H), 6.90-6.65 (m, 4 H),5.78 (s, 2 H), 4.80 (s, 2 H); MS: m/z 375 (M⁺+1).

Example 1002-[(3-Fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (219)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-fluorobenzylchloride (0.190 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 169 mg of the product 219. ¹H NMR (DMSO-d₆) δ 11.39 (s, 2 H),7.65-7.40 (m, 3 H), 7.35-7.20 (m, 1 H), 7.20-6.90 (m, 6 H), 6.90-6.65(m, 4 H), 5.80 (s, 2 H), 4.85 (s, 2 H); MS: m/z 363 (M⁺+1).

Example 1012-[(3-Bromobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (220)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-bromobenzylchloride (0.201 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 298 mg of the product 220. ¹H NMR (DMSO-d₆) δ 11.30 (s, 2 H),7.95-7.80 (m, 1 H), 7.75-7.50 (m, 2 H), 7.50-7.35 (m, 1 H), 7.15-6.90(m, 6 H), 6.90-6.60 (m, 4 H), 5.78 (s, 2 H), 4.80 (s, 2 H); MS: m/z 423(M⁺+1).

Example 1022-[(3,5-Ditrifluoromethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (221)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and3,5-ditrifluoromethylbenzyl chloride (417 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 278 mg of the product 221. ¹H NMR (DMSO-d₆)δ 11.43 (s, 2 H), 8.40 (s, 2 H), 8.20 (s, 1 H), 7.15-6.85 (m, 6 H),6.90-6.55 (m, 4 H), 5.77 (s, 2 H), 4.82 (s, 2 H); MS: m/z 481 (M⁺+1).

Example 1032-[(2-Iodobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (222)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-iodobenzylchloride (396 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 270 mg of the product 222. ¹H NMR (DMSO-d₆) δ 11.43 (s, 2 H), 8.00(d, 1 H), 7.82 (d, 1 H), 7.48 (t, 1 H), 7.30-7.00 (m, 7 H), 7.00-6.80(m, 4 H), 5.82 (s, 2 H), 4.88 (s, 2 H); MS: m/z 471 (M⁺+1).

Example 1042-[(4-Methoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (223)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-methoxybenzylchloride (0.213 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 167 mg of the product 223. ¹H NMR (DMSO-d₆) δ 11.24 (s, 2 H), 7.50(d, 2 H), 7.20-6.90 (m, 8 H), 6.90-6.65 (m, 4 H), 5.78 (s, 2 H), 4.78(s, 2 H), 3.78 (s, 3 H); MS: m/z 375 (M⁺+1).

Example 1052-[(4-Benzyloxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (224)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-benzyloxybenzylchloride (365 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 194 mg of the product 224. ¹H NMR (DMSO-d₆) δ 11.28 (s, 2 H),7.60-7.25 (m, 7 H), 7.20-6.95 (m, 8 H), 6.95-6.70 (m, 4 H), 5.75 (s, 2H), 5.25 (s, 2 H), 4.80 (s, 2 H); MS: m/z 451 (M⁺+1).

Example 1062-[(3,4-Dibenzyloxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (225)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and3,4-dibenzyloxybenzyl chloride (532 mg, 1.57 mmol) in abs. EtOH (2 mL)is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 149 mg of the product 225. MS: m/z 557(M⁺+1).

Example 1072-[(2-Methylnaphthalen-1-yl)methylthio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (226)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and1-chloromethyl-2-methyl-naphthalene (299 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 229 mg of the product 226. ¹H NMR (DMSO-d₆)δ 11.40 (s, 2 H), 8.36 (d, 1 H), 8.10-7.80 (m, 2 H), 7.80-7.30 (m, 3 H),7.30-6.75 (m, 10 H), 5.90 (s, 2 H), 5.30 (s, 2 H), 2.62 (s, 3 H); MS:m/z 409 (M⁺+1).

Example 1082-[(2-Methylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (227)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-methylbenzylchloride (0.204 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 174 mg of the product 227. ¹H NMR (DMSO-d₆) δ 11.28 (s, 2 H), 7.68(m, 1 H), 7.55-7.20 (m, 3 H), 7.20-7.00 (m, 6 H), 7.00-6.90 (m, 4 H),5.82 (s, 2 H), 4.81 (s, 2 H), 2.44 (s, 3 H); MS: m/z 359 (M⁺+1).

Example 1092-[(4-Trifluoromethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (228)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and4-trifluoromethylbenzyl chloride (0.232 mL, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 262 mg of the product 228. ¹H NMR (DMSO-d₆)δ 11.42 (s, 2 H), 7.95-7.90 (m, 4 H), 7.15-6.90 (m, 6 H), 6.90-6.65 (m,4 H), 5.77 (s, 2 H), 4.92 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 1102-[(2-Chloro-4-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (229)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and2-chloro-4-fluorobenzyl chloride (281 mg, 1.57 mmol) in abs. EtOH (2 mL)is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 249 mg of the product 229. ¹H NMR (DMSO-d₆)δ 11.35 (s, 2 H), 8.00-7.80 (m, 1 H), 7.75-7.60 (m, 1 H), 7.55-7.35 (m,1 H), 7.20-7.00 (m, 6 H), 7.00-6.85 (m, 4 H), 5.80 (s, 2 H), 4.90 (s, 2H); MS: m/z 397 (M⁺+1).

Example 1112-[(2,5-Dimethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (230)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,5-dimethylbenzylchloride (0.269 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C.for 24 h. The reaction mixture is cooled to RT, evaporated to dryness,and the residue suspended in Et₂O. The insoluble material is filtered togive 171 mg of the product 230. ¹H NMR (DMSO-d₆) δ 11.20 (s, 2 H), 7.38(s, 1 H), 7.30-7.00 (m, 8 H), 7.00-6.85 (m, 4 H), 5.82 (s, 2 H), 4.75(s, 2 H), 2.40 (s, 3 H), 2.30 (s, 3 H); MS: m/z 373 (M⁺+1).

Example 1122-[(2-Chloro-6-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (231)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and2-chloro-6-fluorobenzyl chloride (0.204 mL, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 174 mg of the product 231. ¹H NMR (DMSO-d₆)δ 11.40 (s, 2 H), 7.70-7.30 (m, 3 H), 7.25-6.90 (m, 10 H), 5.88 (s, 2H), 4.90 (s, 2 H); MS: m/z 397 (M⁺+1).

Example 1132-[(Anthracen-9-yl)methylthio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (232)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and9-chloromethylanthracene (256 mg, 1.57 mmol) in abs. EtOH (2 mL) isheated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 179 mg of the product 232. ¹H NMR (DMSO-d₆)δ 11.35 (s, 2 H), 8.80 (s, 1 H), 8.64 (d, 2 H), 7.85-7.50 (m, 4 H), 7.38(d, 1 H), 7.30-6.80 (m, 10 H), 6.80-6.65 (m, 4 H), 5.92 (s, 4 H); MS:m/z 445 (M⁺+1).

Example 1142-[(2-Trifluoromethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (233)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and2-trifluoromethylbenzyl chloride (0.229 mL, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 224 mg of the product 233. ¹H NMR (DMSO-d₆)δ 11.41 (s, 2 H), 7.95 (d, 1 H), 7.90-7.75 (m, 2 H), 7.65 (t, 1 H),7.25-6.90 (m, 10 H), 5.85 (s, 2 H), 4.98 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 1152-[(2,3,4,5,6-Pentamethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (234)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and2,3,4,5,6-pentamethylbenzyl chloride (309 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 186 mg of the product 234. ¹H NMR (DMSO-d₆)δ 11.20 (s, 2 H), 7.25-6.95 (m, 10 H), 5.85 (s, 2 H), 4.84 (s, 2 H),2.38 (s, 6 H), 2.20 (s, 9 H); MS: m/z 415 (M⁺+1).

Example 1162-[(2-Bromobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (235)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-bromobenzylchloride (327 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 400 mg of the product 235. ¹H NMR (DMSO-d₆) δ 11.52 (s, 2 H), 7.86(d, 1 H), 7.78 (d, 1 H), 7.55-7.30 (m, 2 H), 7.20-7.00 (m, 6 H),7.00-6.85 (m, 4 H), 5.83 (s, 2 H), 4.95 (s, 2 H); MS: m/z 424 (M⁺+1).

Example 1172-[(2,3,5,6-Tetramethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (236)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and2,3,5,6-tetramethylbenzyl chloride (287 mg, 1.57 mmol) in abs. EtOH (2mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT,evaporated to dryness, and the residue suspended in Et₂O. The insolublematerial is filtered to give 177 mg of the product 236. ¹H NMR (DMSO-d₆)δ 11.33 (s, 2 H), 7.25-6.95 (m, 11 H), 5.86 (s, 2 H), 4.84 (s, 2 H),2.35 (s, 6 H), 2.21 (s, 6 H); MS: m/z 401 (M⁺+1).

Example 1182-[(4-Bromobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (237)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-bromobenzylchloride (327 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 290 mg of the product 237. ¹H NMR (DMSO-d₆) δ 11.30 (s, 2 H), 7.65(d, 2 H), 7.58 (d, 2 H), 7.15-6.95 (m, 6 H), 6.90-6.65 (m, 4 H), 5.78(s, 2 H), 4.80 (s, 2 H); MS: m/z 424 (M⁺+1).

Example 1192-[(2,5-Dichlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (238)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,5-dichlorobenzylchloride (327 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 175 mg of the product 238. ¹H NMR (DMSO-d₆) δ 11.50 (s, 2 H), 8.00(s, 1 H), 7.70-7.50 (m, 2 H), 7.20-7.00 (m, 6 H), 6.95-6.80 (m, 4 H),5.81 (s, 2 H), 4.90 (s, 2 H); MS: m/z 413 (M⁺+1).

Example 1202-[(4-Isopropylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (239)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-isopropylbenzylchloride (264 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 249 mg of the product 239. ¹H NMR (DMSO-d₆) δ 11.24 (s, 2 H), 7.52(d, 2 H), 7.32 (d, 2 H), 7.20-6.90 (m, 6 H), 6.90-6.70 (m, 4 H), 5.77(s, 2 H), 4.78 (s, 2 H), 3.02-3.85 (m, 1 H), 1.22 (d, 6 H); MS: m/z 387(M⁺+1).

Example 1212-[(2,4-Dimethylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (240)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2,4-dimethylbenzylchloride (243 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 177 mg of the product 240. ¹H NMR (DMSO-d₆) δ 11.18 (s, 2 H),7.20-6.80 (m, 13 H), 5.80 (s, 2 H), 4.88 (s, 2 H), 2.41 (s, 3H), 2.30(s, 3 H); MS: m/z 373 (M⁺+1).

Example 1222-[(3-Phenoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (241)

A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-phenoxybenzylchloride (343 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for24 h. The reaction mixture is cooled to RT, evaporated to dryness, andthe residue suspended in Et₂O. The insoluble material is filtered togive 350 mg of the product 241. ¹H NMR (DMSO-d₆) δ 11.25 (s, 2 H),7.55-7.30 (m, 6 H), 7.30-7.25 (m, 1 H), 7.25-7.10 (m, 1 H), 7.15-6.90(m, 6H), 6.90-6.70 (m, 4 H), 5.79 (s, 2 H), 4.81 (s, 2 H); MS: m/z 437(M⁺+1).

Example 123 2-Phenethyl-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (243)

A mixture of cis-1,2-diphenylethane-1,2-diamine (1) (1.0 g, 4.7 mmol)and 3-phenyl-propionimidic acid methyl ester hydrochloride (242) (0.94g, 4.7 mmol) in EtOH (10 mL) is heated at 80° C. overnight. The solventis removed by rotary evaporation, and the residue dissolved indichloromethane, and the solution washed with sodium carbonate, brine,then dried (MgSO₄) and filtered. The filtrate is rotary evaporated togive 1.2 g of impure product 243.

A mixture of impure product (1.0 g, 2.76 mmol), diethylamine (0.442 mL,3.03 mmol), 4-dimethylaminopyridine (10 mg), anddi-tert-butyl-dicarbonate (0.66 g, 3.03 mmol) in dichloromethane (50 mL)is stirred at RT for 2 days. The mixture is washed with water, brine,then dried (MgSO₄) and filtered. The filtrate is rotary evaporated andthe residue purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-60:40) gives 0.84 g of the N-Boc derivative ofthe product. ¹H NMR (CDCl₃) δ 7.50-7.20 (m, 5 H), 7.10-6.90 (m, 6 H),6.90-6.85 (m, 2 H), 6.75-6.65 (m, 2 H), 5.55-5.35 (m, 2 H), 3.50-3.10(m, 4 H), 1.19 (s, 9 H); MS: m/z 427 (M⁺+1).

Hydrogen chloride is bubbled into a solution of the above N-Bocderivative (0.84 g, 1.97 mmol) in EtOAc (50 mL) for 1 min, and themixture stirred at RT overnight. The solvent is rotary evaporated, andthe residue recrystallized from dichloromethane:Et₂O to give 0.54 g ofthe product 243. ¹H NMR (DMSO-d₆) δ 10.90 (s, 2 H), 7.60-7.30 (m, 5 H),7.15-6.90 (m, 6 H), 6.90-6.65 (m, 4 H), 5.71 (s, 2 H), 3.25-3.05 (m, 4H); LC/MS: 3.15 min, m/z 327 (M⁺+1).

Example 1242-Phenethyl-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazolehydrochloride (244)

A mixture of cis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5) (0.5 g,2.01 mmol) and 3-phenylpropionimidic acid methyl ester hydrochloride(242) (0.402 g, 2.01 mmol) in EtOH (20 mL) is heated at 90° C. for 2days. The solvent is removed by rotary evaporation to give impureproduct 244.

A mixture of the above impure product, triethylamine (0.310 mL, 2.23mmol), 4-dimethylaminopyridine (10 mg), and di-tert-butyl-dicarbonate(0.486 g, 2.21 mmol) in dichloromethane (50 mL) is stirred at RT for 3days. The mixture is washed with water, brine, dried (MgSO₄), andfiltered. The filtrate is rotary evaporated and the residue purified bychromatography on silica gel; elution with heptane:EtOAc (70:30) gives0.78 g of the N-Boc derivative of the product. ¹H NMR (CDCl₃) δ7.45-7.30 (m, 3 H), 7.30-7.15 (m, 2 H), 7.05-6.90 (m, 2 H), 6.75-6.35(m, 6 H), 5.55-5.30 (m, 2 H), 3.55-3.05 (m, 4 H), 1.23 (s, 9 H); MS: m/z463 (M⁺+1).

Hydrogen chloride is bubbled into a solution of the above N-Bocderivative (0.78 g, 1.69 mmol) in EtOAc (25 mL) for 1 min, and themixture stirred at RT overnight. The solvent is rotary evaporated, andthe residue recrystallized from dichloromethane:Et₂O to give 0.52 g ofthe product 244. ¹H NMR (DMSO-d₆) δ 10.98 (s, 2 H), 7.20-7.05 (m, 2 H),7.00-6.85 (m, 2 H), 6.80-6.60 (m, 4 H), 5.77 (s, 2 H), 3.25-3.10 (m, 4H); MS: m/z 363 (M⁺+1).

Example 1252-Phenethyl-cis-4,5-bis-(4-fluorophenyl)-4,5-dihydro-1H-imidazolehydrochloride (245)

A mixture of cis-1,2-bis-(4-fluorophenyl)ethane-1,2-diamine (6) (0.5 g,2.01 mmol) and 3-phenylpropionimidic acid methyl ester hydrochloride(242) (0.402 g, 2.01 mmol) in EtOH (20 mL) is heated at 90° C.overnight. The solvent is removed by rotary evaporation, and the residueis dissolved in dichloromethane, and the solution is washed with water,brine, then dried (MgSO₄) and filtered. The filtrate is rotaryevaporated to give 0.78 g of impure product 245.

A mixture of the above impure product (0.78 g, 2.15 mmol), triethylamine(0.300 mL, 2.15 mmol), 4-dimethylaminopyridine (10 mg), anddi-tert-butyl-dicarbonate (0.520 g, 2.37 mmol) in dichloromethane (10mL) is stirred at RT for 4 h. The mixture is washed with water, brine,then dried (MgSO₄) and filtered. The filtrate is rotary evaporated andthe residue purified by chromatography on silica gel; elution withheptane:EtOAc (70:30) gives 0.65 g of the N-Boc derivative of theproduct. ¹H NMR (CDCl₃) δ 7.45-7.20 (m, 5H), 6.85-6.55 (m, 8 H),5.55-5.30 (m, 2 H), 3.50-3.10 (m, 4 H), 1.22 (s, 9 H)

Hydrogen chloride is bubbled into a solution of the above N-Bocderivative (0.64 g, 1.38 mmol) in EtOAc (20 mL) for 0.5 min, and themixture stirred at RT overnight. The solvent is rotary evaporated, andthe residue recrystallized from dichloromethane:Et₂O to give 0.409 g ofthe product 245. ¹H NMR (CDCl₃) δ 11.09 (s, 2 H), 7.50-7.40 (m, 2 H),7.40-7.30 (m, 3 H), 6.70-6.55 (t, 4 H), 6.50-6.35 (m, 4 H), 5.25 (s, 2H), 3.28 (m, 4 H); MS: m/z 363 (M⁺+1).

Example 1262-Phenethyl-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (246)

A mixture of cis-1,2-diphenylpropane-1,2-diamine (16) (0.300 g, 1.33mmol) and 3-phenylpropionimidic acid methyl ester hydrochloride (242)(0.246 g, 1.33 mmol) in EtOH (30 mL) is heated at 90° C. for 2 days. Thesolvent is removed by rotary evaporation to give impure product 246.

A mixture of the above impure product, triethylamine (0.203 mL, 1.46mmol), 4-dimethylaminopyridine (10 mg), and di-tert-butyl-dicarbonate(0.319 g, 1.46 mmol) in dichloromethane (50 mL) is stirred at RT for 3days. The mixture is washed with water, brine, then dried (MgSO₄) andfiltered. The filtrate is rotary evaporated and the residue purified bychromatography on silica gel; elution with heptane:EtOAc (70:30) gives0.49 g of the N-Boc derivative of the product. ¹H NMR (CDCl₃) δ7.45-7.20 (m, 5 H), 7.05-6.90 (m, 8 H), 6.90-6.80 (m, 2 H), 4.97 (s, 1H), 3.50-3.10 (m, 4 H), 1.71 (s, 3 H), 1.18 (s, 9 H); LC/MS: 3.62 min,m/z 441 (M⁺+1).

Hydrogen chloride is bubbled into a solution of the above N-Bocderivative (0.49 g, 1.11 mmol) in EtOAc (50 mL) for 1 min, and themixture stirred at RT overnight. The solvent is rotary evaporated, andthe residue recrystallized from dichloromethane:Et₂O to give 0.290 g ofthe product 246. ¹H NMR (CDCl₃) δ 11.35 (s, 1 H), 10.78 (s, 1 H),7.50-7.30 (m, 2 H), 7.30-7.15 (m, 3 H), 7.00-6.80 (m, 6 H), 6.70-6.55(D, 2 H), 6.50-6.35 (d, 2 H), 4.75 (s, 1 H), 3.30-3.10 (m, 4 H), 1.61(s, 3 H); LC/MS: 2.83 min, m/z 341 (M⁺+1).

Example 1272-Phenethyl-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (248)

Step 1

A mixture of cis-1,2-di-(3-fluorophenyl)propane-1,2-diamine (23) (0.202g, 0.77 mmol) and 3-phenylpropionimidic acid methyl ester hydrochloride(242) (0.169 g, 847 mmol) in EtOH (30 mL) is heated at 90° C. forovernight. The solvent is removed by rotary evaporation to give impureproduct 248.

Step 2

2-Phenethyl-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydroimidazole-1-carboxylicacid, tert-butyl ester (247)

A mixture of the above impure product, triethylamine (0.128 mL, 0.924mmol), 4-dimethylaminopyridine (10 mg), and di-tert-butyl-dicarbonate(0.202 g, 0.924 mmol) in dichloromethane (30 mL) is stirred at RTovernight. The mixture is washed with water, brine, then dried (MgSO₄)and filtered. The filtrate is rotary evaporated and the residue purifiedby chromatography on silica gel; elution with heptane:EtOAc (70:30)gives 0.33 g of the product 247. ¹H NMR (CDCl₃) δ 7.45-7.15 (m, 5 H),7.05-6.90 (m, 2 H), 6.85-6.55 (m, 4 H), 6.55-6.35 (m, 2 H), 4.93 (s, 1H), 3.50-3.10 (m, 4 H), 1.68 (s, 3 H), 1.21 (s, 9 H); LC/MS: 3.30 min,m/z 477 (M⁺+1).

Step 3

2-Phenethyl-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (248)

Hydrogen chloride is bubbled into a solution of 247 (0.31 g, 0.65 mmol)in EtOAc (30 mL) for 0.5 min, and the mixture stirred at RT overnight.The solvent is rotary evaporated, and the residue recrystallized fromdichloromethane:Et₂O to give 0.186 g of the product 248. ¹H NMR(DMSO-d₆) δ 11.14 (s, 1 H), 10.93 (s, 1 H), 7.50-7.30 (m, 5 H),7.20-7.00 (m, 2 H), 7.00-6.50 (m, 6 H), 5.27 (s, 1 H), 3.15-3.10 (m, 4H), 1.82 (s, 3 H); LC/MS: 2.80 min, m/z 377 (M++1).

Example 1282-[2-(3,4-Difluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole(250)

Step 1

3-(3,4-Difluorophenyl)propionic acid, ethyl ester (249)

To a solution of 3-(3,4-difluorophenyl)propionic acid (1.0 g, 5.4 mmol)in EtOH (10 mL) is added dropwise acetyl chloride (1.0 mL, 14.1 mmol),and the solution is stirred at RT for 2 h. The solvent is rotaryevaporated, and the residue purified by chromatography on silica gel;elution with heptane:EtOAc (4:1) gives 0.99 g of the product 249. ¹H NMR(CDCl₃) δ 7.10-6.85 (m, 3 H), 4.13 (q, 2 H), 2.90 (t, 2 H), 3.35-2.59(t, 2 H), 1.23 (t, 2 H); MS: m/z 215 (M⁺+1).

Step 2

2-[2-(3,4-Difluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole(250)

To a solution of cis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5) (248mg 1.0 mmol) in toluene (6 mL) is added 2.0M trimethylaluminum intoluene (1.0 mL, 2.0 mmol). The solution is stirred at RT for 20 min,and intermediate 249 (214 mg, 1 mmol) is added, and the solution isheated at 80° C. overnight. The reaction is quenched by the addition ofsat. sodium bicarbonate solution, and water and EtOAc are added. Theorganic layer is separated, washed with brine, then dried (Na₂SO₄), andfiltered. The filtrate is evaporated, and the residue triturated withEt₂O to give 118 mg of the product 250. ¹H NMR (CDCl₃) δ 7.70 (s, 2 H),7.30-6.40 (m, 10 H), 5.55-5.00 (m, 2 H), 3.35-3.05 (m, 2 H), 2.75 (t, 2H); MS: m/z 399 (M⁺+1).

Example 1292-[2-(2-Chlorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole(251)

To a solution of cis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5)(248.3 mg 1 mmol) in toluene (6 mL) is added 2.0 M trimethylaluminum intoluene (1.0 mL, 2.0 mmol). The solution is stirred at RT for 20 min,and 3-(2-chlorophenyl)propionitrile (0.145 mL, 1 mmol) is added, and thesolution is heated at 70° C. for 18 h. The reaction is quenched by theaddition of sat. sodium bicarbonate solution, and water and EtOAc areadded. The organic layer is separated, washed with brine, dried(Na₂SO₄), and filtered. The filtrate is evaporated, and the residue ispurified by chromatography on silica gel; elution with heptane:EtOAc(5:1) and then with dichloromethane:MeOH (95:5) gives 12 mg of theproduct 251. ¹H NMR (CDCl₃) δ 7.70 (s, 2 H), 7.50-7.10 (m, 3 H),7.10-6.80 (m, 2 H), 6.80-6.40 (m, 5 H), 5.35 (s, 3 H), 3.23 (t, 2 H),2.90 (t, 2 H); MS: m/z 397 (M⁺+1).

Example 1302-(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1-phenylethan-1-ol(255)

Step 1

2-Methyl-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acid,tert-butyl ester (253)

To a solution of 2-methyl-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(252) (4.27 g, 18.1 mmol) in dichloromethane (20 mL) is addedtriethylamine (5.2 mL, 37.8 mmol), di-tert-butyl-dicarbonate (5.2 mL,22.7 mmol), and 4-dimethylaminopyridine (50 mg), and the mixture isstirred at RT overnight. The reaction mixture is washed with water,brine, then dried (MgSO₄), filtered, and the filtrate is rotaryevaporated. The residue is crystallized from Et₂O to give 5.4 g of theproduct 253. ¹H NMR (CDCl₃) δ 7.10-6.85 (m, 10 H), 6.85-6.70 (m, 2 H),5.60-5.30 (m, 2 H), 2.60 (s, 3 H), 1.20 (s, 9 H); MS: m/z 337 (M⁺+1).

Step 2

2-[(2-Hydroxy-2-phenyl)ethyl]-cis-4,5-diphenyl)-4,5-dihydroimidazole-1-carboxylicacid, tert-butyl ester (254)

To a cold (−70° C.) solution of 253 (336 mg, 1 mmol) in THF is added2.5M n-butyl lithium in hexane (0.44 mL, 1.1 mmol), and the mixture isstirred for 1 h at −70° C. To the reaction mixture is added benzaldehyde(0.11 mL, 1.1 mmol), and the mixture is stirred for 1 h at −70° C. and0.5 h at RT. To the reaction mixture is added ammonium chloridesolution, EtOAc, and the organic layer is separated, and washed withbrine, dried (MgSO₄), and filtered. The filtrate is rotary evaporated,and the residue purified by chromatography on silica gel; elution withdichloromethane:EtOAc (9:1) gives 230 mg of the product 254. ¹H NMR(CDCl₃) δ 7.60-7.50 (m, 2 H), 7.50-7.25 (m, 3 H), 7.15-6.90 (m, 8 H),6.80-6.70 (m, 2 H), 5.70-5.50 (m, 1 H), 5.50-5.20 (m, 3 H), 3.65-3.40(m, 1 H), 3.30-3.20 (m, 1 H), 1.17 (s, 9 H); MS: m/z 443 (M⁺+1).

Step 3

2-(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1-phenylethan-1-ol(255)

To a cold (0° C.) solution of 254 (442 mg, 1 mmol) in THF is added 4NHCl in dioxane (2.0 mL, 8.0 mmol), and the mixture is stirred at 0° C.for 20 min and at RT for 2 days. To the reaction mixture is added EtOAc,and the mixture washed with NaHCO₃, the organic layer is separated, andwashed with brine, dried (MgSO₄), and filtered. The filtrate is rotaryevaporated, and the residue purified by chromatography on silica gel;elution with dichloromethane:MeOH:NH₄OH (9:1:0.1) gives 130 mg of theproduct 255. ¹H NMR (CDCl₃) δ 7.60-7.20 (m, 5 H), 7.10-6.70 (m, 11 H),5.45-5.20 (m, 3 H), 2.82 (d, 2 H); MS: m/z 343 (M⁺+1).

Example 1312-(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethan-1-one(258)

Step 1

2-[2-(4-Fluorophenyl)-2-hydroxyethyl]-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (256)

To a cold (−70° C.) solution of2-methyl-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acid,tert-butyl ester (253) (3.36 g, 10.0 mmol) in THF is added 1.6M n-butyllithium in hexane (6.9 mL, 11.0 mmol), and the mixture is stirred for 1h at −70° C. To the reaction mixture is added 4-fluorobenzaldehyde (1.18mL, 11.0 mmol), and the mixture is stirred for 1 h at −70° C. and 1 h atRT. To the reaction mixture is added ammonium chloride solution, EtOAc,and the organic layer is separated, and washed with brine, dried(MgSO₄), and filtered. The filtrate is rotary evaporated, and theresidue purified by chromatography on silica gel; elution withdichloromethane:EtOAc (9:1) gives 2.11 g of the product 256. ¹H NMR(CDCl₃) δ 7.60-7.45 (m, 2 H), 7.15-6.90 (m, 10 H), 6.85-6.60 (m, 2 H),5.70-5.20 (m, 4 H), 3.60-3.10 (m, 2 H), 1.18 (s, 9 H); MS: m/z 461(M⁺+1).

Step 2

2-[2-(4-Fluorophenyl)-2-oxoethyl]-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (257)

To a cold (−70° C.) solution of oxalyl chloride (0.27 mL, 3.06 mmol) indichloromethane (15 mL) is added DMSO (0.32 mL, 6.11 mmol) followed bythe alcohol 256 (1.28 g, 2.48 mmol) in dichloromethane (5 mL). Themixture is stirred for at −70° C. solution 15 min., and triethylamine(1.03 mL, 13.9 mmol) is added and the mixture is allowed to come to RTand is stirred for 4 h. The reaction mixture is washed with water,brine, then dried (MgSO₄), and filtered. The filtrate is rotaryevaporated, and the residue is recrystallized from Et₂O to give 1.02 gof the product 257. ¹H NMR (CDCl₃) δ 10.60 (s, 1 H), 8.10-7.95 (m, 2 H),7.10-6.90 (m, 12 H), 6.90-6.70 (m, 2 H), 5.40 (s, 2 H), 1.25 (s, 9 H);MS: m/z 459 (M⁺+1).

Step 3

2-(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethan-1-one(258)

To a cold (0° C.) solution of 257 (458 mg, 1.0 mmol) in dichloromethane(25 mL) is added TFA (1.5 mL). The reaction mixture is stirred for 20min. at 0° C., and at RT for 30 min. The solution is poured into coldsat. sodium bicarbonate solution, and the mixture extracted with EtOAc.The organic layer is separated, dried (MgSO₄), and filtered. Thefiltrate is rotary evaporated, and the residue is recrystallized fromEt₂O to give 170 mg of the product 258. ¹H NMR (CDCl₃) δ 10.60-8.80 (bs,1 H), 8.00-7.80 (m, 2 H), 7.20-7.00 (m, 9 H), 7.00-6.85 (m, 4 H), 5.50(bs, 1 H), 5.30 (s, 2 H); MS: m/z 359 (M⁺+1).

Example 1322-[2(E)-(4-Fluorophenyl)vinyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(259)

To a cold (0° C.) solution of2-[2-(4-fluorophenyl)-2-hydroxyethyl]-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylicacid, tert-butyl ester (256) (690 mg, 1.5 mmol) in dichloromethane (2mL) is added TFA (2 mL). The reaction mixture is stirred at RTovernight. Reaction mixture is rotary evaporated and the residuepurified by chromatography on silica gel; elution withdichloromethane:MeOH (9:1) gives 110 mg of the product 259. ¹H NMR(CDCl₃) δ 8.10 (d, 1 H), 7.60-7.35 (m, 2 H), 7.15-6.85 (m, 9 H),6.85-6.60 (m, 4 H), 5.20 (s, 2 H); MS: m/z 343 (M⁺+1).

Example 133

This Example illustrates the syntheses of a few of the compounds of thisinvention by way of a solid phase synthetic techniques. In this Example,the following procedure is employed to make a variety of compounds ofthis invention following the steps as set forth in Scheme 9.

A mixture of cis-1,2-diphenylethane-1,2-diamine (1) (5 mmol) indichloromethane and p-nitrophenyl carbonate Wang resin (1 g, 1.32mmol/g) is shaken overnight, the resin filtered and washed withdichloromethane. A suspension of the monocarbamoylated resin (0.20 g,0.26 mmol) is treated with a substituted 3-phenylpropionic acid (0.78mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.78mmol) in DMF (6 mL), and the mixture is shaken overnight at RT. Theresin is filtered, washed with DMF, and the substituted3-phenylpropanamide derivative is cleaved from the resin with 50%TFA/DMF (or methylene chloride) at RT for 1.5 h. The solvents areevaporated, and the residue is dissolved in trimethylsilylpolyphosphate/dichloromethane solution (1:4), and the solution ismicrowaved at 140° C. for 2×4 min to effect imidazoline ring formation.The mixture is diluted with dichloromethane, washed with water, sat.sodium bicarbonate, brine, then dried (Na₂SO₄), and filtered. Thefiltrate is rotary evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH (8:2) oron reversed phase silica gel; elution with acetonitrile:water/0.5% TFA(80:20) gives the product.

The compounds so prepared are summarized in Table 1, which are alsoidentified by a compound number. Also summarized in Table 1 are theamounts of the compound formed, the LC/MS retention time, m/e ion peak,and the substituted 3-phenylpropionic acid employed to make therespective compound. Also listed are two examples which utilizedrespectively, 5-phenyl-butanoic acid and 5-phenyl-pentanoic acid to makethe corresponding imidazoline derivatives, Compound Nos. 267D and 267E.

TABLE 1 Compound Amount (mg) LC/MS retention time LC/MS m/e (M⁺ + 1). #Substituted (R_(a)) 3-phenylpropionic acid 2602-[2-(2-Methoxyphenyl)ethyl]-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate 20 mg 2.89 min 357 3-(2-methoxyphenyl)propionic acid261 2-[2-(3,4-Dimethoxyphenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate 26 mg 2.54 min 3873-(3,4-dimethoxyphenyl)propionic acid 2622-[2-(4-Methylphenyl)ethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazole17 mg 2.77 min 341 3-(4-methylphenyl)propionic acid 2632-[2-(2-Methylphenyl)ethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazole21 mg 2.74 min 341 3-(2-methylphenyl)propionic acid 2642-[2-(4-Methoxyphenyl)ethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate  7 mg 2.70 min 357 3-(4-methoxyphenyl)propionic acid265 2-[2-(3,4-Difluorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 26 mg 2.72 min 3633-(3,4-difluorophenyl)propionic acid 2662-[2-(4-Trifluoromethylphenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate 35 mg 3.25 min 3953-(4-trifluoromethylphenyl)propionic acid 2672-[2-[(2S)-Phenyl)propyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 58 mg 3.15 min 341 (3S)-3-phenylbutanoic acid 267A2-[2-Methyl-(2S)-phenyl)-propyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate n.a. n.a. 3553-Methyl-(3S)-3-phenylbutanoic acid 267B2-[2,2-Diphenylethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 403 3,3-Diphenylpropanoic acid 267C2-[1-Methyl-2-phenylethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 341 2-Methyl-3-phenylpropanoic acid 267D2-[3-Phenyl-propyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 341 4-phenyl-butanoic acid 267E2-[4-Phenyl-butyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 355 4-phenyl-pentanoic acid 2682-[2-(2-Fluorophenyl)ethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 56 mg 2.70 min 345 3-(2-fluorophenyl)propionic acid 2692-[2-(3-Fluorophenyl)ethyl]-cis- 4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate 60 mg 2.68 min 345 3-(3-fluorophenyl)propionic acid 2702-[2-(4-Fluorophenyl)ethyl]-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 61 mg 2.70 min 345 3-(4-fluorophenyl)propionic acid 2712-[2-(2-Chlorophenyl)ethyl]-cis- 4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate 11 mg 2.80 min 361 3-(2-chlorophenyl)propionic acid271A 2-[2-(3-Chlorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate n.a. n.a. 3613-(3-chlorophenyl)propionic acid 271B 2-[2-(4-Chlorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate n.a. n.a. 3613-(4-chlorophenyl)propionic acid 2722-[2-(3,4-Dichlorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole trifluoroacetate 28 mg 2.99 min395 3-(3,4-dichlorophenyl)propionic acid 2732-[2-(3-Methylphenyl)ethyl]-cis- 4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate 66 mg 2.81 min 341 3-(3-methylphenyl)propionic acidn.a. = not available

Example 134

The procedure as set forth in Example 133 is essentially repeated inthis Example except that a substituted phenylacetic acid (0.78 mmol) isemployed in the place of a substituted 3-phenylpropionic acid. Thesubstituted phenylacetamide derivative so formed is then cleaved inaccordance with the procedures of Example 133 and the product isisolated.

The compounds so prepared are summarized in Table 2, which are alsoidentified by a compound number. Also summarized in Table 2 are theamounts of the compound formed, the LC/MS retention time, m/e ion peak,and the substituted phenylacetic acid employed to make the respectivecompound. An example has also been included in this Table which utilized2-indanyl carboxylic acid to make the corresponding imidazoline,compound 283D.

TABLE 2 Compound Amount (mg) LC/MS retention time LC/MS m/e (M⁺ + 1). #Substituted phenylacetic acid 2742-(3-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate 14 mg 2.95 min 347 3-chlorophenylacetic acid 274A2-(2-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 347 2-chlorophenylacetic acid 274B2-(4-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 347 4-chlorophenylacetic acid 2752-(4-Trifluoromethylbenzyl)-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 18 mg 2.90 min 381 4-trifluoromethylphenylacetic acid276 2-(2,5-Dimethoxybenzyl)-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 35 mg 3.85 min 373 2,5-dimethoxyphenylacetic acid 2772-(2,3-Dimethoxybenzyl)-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 36 mg 2.90 min 373 2,3-dimethoxyphenylacetic acid 2782-(2-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- imidazoletrifluoroacetate 10 mg 2.85 min 331 2-fluorophenylacetic acid 278A2-(3-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- imidazoletrifluoroacetate n.a. n.a. 331 3-fluorophenylacetic acid 2792-(4-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate 27 mg 2.87 min 331 4-fluorophenylacetic acid 2802-(2-Bromobenzyl)-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate 19 mg 4.14 min 393 2-bromophenylacetic acid 2812-(2,4-Difluorobenzyl)-cis-4,5-diphenyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 10 mg 3.95 min 349 2,4-difluorophenylacetic acid 2822-(3,4-Difluorobenzyl)-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate  6 mg 2.87 min 349 3,4-difluorophenylacetic acid 282A2-(2,3-Difluorobenzyl)-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 349 2,3-difluorophenylacetic acid 2832-(2-Methylbenzyl)-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate 28 mg 3.77 min 327 2-methylphenylacetic acid 283A2-(4-Methylbenzyl)-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 327 4-methylphenylacetic acid 283B2-(1-phenyl-(1R)-ethyl)-cis-4,5-diphenyl-4,5- dihydro-1H-imidazoletrifluoroacetate n.a. n.a. 327 1-phenyl-ethanoic acid 283C2-Indan-2-ylmethyl-cis-4,5-diphenyl-4,5-dihydro- 1H-imidazoletrifluoroacetate n.a. n.a. 353 2-Indanylacetic acid 283D2-Indan-2-yl-4,5-diphenyl-4,5-dihydro- 1H-imidazole trifluoroacetaten.a. n.a. 339 2-Indanyl-carboxylic acid n.a. = not available

Example 135

The procedure as set forth in Example 133 is essentially repeated inthis Example except that a mixture ofcis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5) (5 mmol) is employedin the place of a mixture of cis-1,2-diphenylethane-1,2-diamine (1) (5mmol). The substituted 3-phenylpropionamide derivative so formed is thencleaved in accordance with the procedures of Example 133 and thecompound is isolated.

The compounds so prepared are summarized in Table 3, which are alsoidentified by a compound number. Also summarized in Table 3 are theamounts of the compound formed, the LC/MS retention time, m/e ion peak,and the substituted 3-phenylpropionic acid employed to make therespective compound.

TABLE 3 Product Amount (mg) LC/MS retention time LC/MS m/e (M⁺ + 1). #Substituted 3-phenylpropionic acid 2842-[2-(2-Fluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate  7 mg 3.15 min 3813-(2-fluorophenyl)propionic acid 2852-[2-(3-Fluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 10 mg 3.15 min 3813-(3-fluorophenyl)propionic acid 2862-[2-(4-Fluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 16 mg 3.14 min 3813-(4-fluorophenyl)propionic acid 2872-[2-(4-Methylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 21 mg 3.20 min 3773-(4-methylphenyl)propionic acid 2882-[2-(3-Methylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 15 mg 3.22 min 3773-(3-methylphenyl)propionic acid 2892-[2-(2-Methylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 17 mg 3.20 min 3773-(2-methylphenyl)propionic acid 2902-[2-(4-Methoxyphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 13 mg 3.12 min 3933-(4-methoxyphenyl)propionic acid 2912-[2-(2-Methoxyphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate  7 mg 2.92 min 3933-(2-methoxypheny)propionic acid 2922-[2-(3,4-Dichlorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate  9 mg 2.97 min 4313-(3,4-dichlorophenyl)propionic acid 2932-[2-(3,4-Dimethoxyphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate  5 mg 2.70 min 4233-(3,4-dimethoxyphenyl)propionic acid 2942-[(2-Thiophen-2-yl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate  2 mg 4.07 min 3693-(Thiophen-2-yl)propionic acid 2952-[2-(4-Trifluoromethylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro- 1H-imidazole trifluoroacetate 15mg 4.15 min 431 3-(4-trifluoromethylphenyl)propionic acid 2962-[2-(3,5-Ditrifluoromethylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro- 1H-imidazole trifluoroacetate 13mg 4.50 min 499 3-(3,5-ditrifluoromethylphenyl)propionic acid

Example 1362-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-ethyl]pyridine(299)

Step 1

3-(Pyridin-2-yl)prop-2(E)-enoic acid methyl ester (297)

To a solution of 2-pyridinecarboxaldehyde (0.476 mL, 5.0 mmol) intoluene (25 mL) is added methyl (triphenylphosphoranylidine)acetate(1.84 g, 5.5 mmol), and the solution is stirred and heated at 90° C. for4 h. The reaction mixture is cooled to RT, diluted with EtOAc, andwashed with water, brine, then dried (MgSO₄), and filtered. The filtrateis rotary evaporated, and the residue is purified by chromatography onsilica gel; elution with EtOAc:MeOH:heptane (25:5:70) gives 0.658 g ofthe product 297 as the mostly trans isomer. ¹H NMR (CDCl₃) δ 8.70 (d, 1H), 7.75-7.70 (m, 2 H), 7.41 (d, 1 H), 7.30 (t, 1 H), 6.90 (d, 1 H),3.85 (s, 3 H); MS: m/z 164 (M⁺+1).

Step 2

3-(Pyridin-2-yl)propionic acid methyl ester (298)

To a solution of 297 (0.658 g, 4.0 mmol) in 1:1 THF:MeOH (14 mL) isadded 10% palladium-on-carbon (98 mg), and the mixture is stirred at RTunder hydrogen for 18 h. The mixture is filtered, and the filtrate isevaporated, and the residue purified by chromatography on silica gel;elution with EtOAc:MeOH:heptane (25:5:70) gives 0.554 g of the product298. ¹H NMR (CDCl₃) δ 8.55 (d, 1 H), 7.59 (t, 1 H), 7.20 (d, 1 H), 7.14(m, 1 H), 3.70 (s, 3 H), 3.13 (t, 2 H), 2.82 (t, 2 H); MS: m/z 166(M⁺+1).

Step 3

2-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-ethyl]pyridine(299)

To a solution of 298 (165 mg, 1.0 mmol) in toluene (8 mL) is added thediamine 1 (212 mg 1.0 mmol) followed by 2.0M trimethylaluminum intoluene (1.2 mL, 1.2 mmol), and the solution is heated at 70° C. for 6h. The reaction is cooled to RT and quenched by the addition of sat.sodium bicarbonate solution, followed by the addition of water andEtOAc. The organic layer is separated, and washed with brine, dried(MgSO₄), and filtered. The filtrate is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH (9:1) gives 99 mg of the product 299. ¹H NMR(CDCl₃) δ 8.56 (d, 1 H), 7.65 (t, 1 H), 7.32 (d, 1 H), 7.17 (m, 1 H),7.0-6.9 (m, 6 H), 6.82-6.80 (m, 4 H), 5.4-5.1 (bs, 2 H), 3.34 (t, 2 H),3.00 (t, 2 H); MS: m/z 328 (M⁺+1).

Example 1373-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-ethyl]pyridine(302)

Step 1

3-(Pyridin-3-yl)prop-2(E)-enoic acid methyl ester (300)

To a solution of 3-pyridinecarboxaldehyde (0.472 mL, 5.0 mmol) intoluene (25 mL) is added methyl (triphenylphosphoranylidine)acetate(1.84 g, 5.5 mmol), and the solution is stirred and heated at 90° C. for3 h. The reaction mixture is cooled to RT, diluted with EtOAc, andwashed with water, brine, then dried (MgSO₄), and filtered. The filtrateis rotary evaporated, and the residue is purified by chromatography onsilica gel; elution with EtOAc:MeOH:heptane (25:5:70) gives 0.355 g ofthe product 300. ¹H NMR (CDCl₃) δ 7.82 (d, 1 H), 7.70-7.60 (m, 2 H),7.50 (m, 1 H), 7.35 (m, 1 H), 6.50 (d, 1 H), 3.80 (s, 3 H); MS: m/z 164(M⁺+1).

Step 2

3-(Pyridin-3-yl)propionic acid methyl ester (301)

To a solution of 300 (0.355 g, 2.2 mmol) in 1:1 THF:MeOH (7 mL) is added10% palladium-on-carbon (53 mg), and the mixture is stirred at RT underhydrogen for 20 h. The mixture is filtered, and the filtrate isevaporated, and the residue purified by chromatography on silica gel;elution with EtOAc:MeOH:heptane (45:5:50) gives 0.124 g of the product301. ¹H NMR (CDCl₃) δ 8.50 (s, 1 H), 7.65 (m, 1 H), 7.45 (m, 1 H), 7.20(m, 1 H), 3.65 (s, 3 H), 2.95 (t, 2 H), 2.65 (t, 2 H); MS: m/z 166(M⁺+1).

Step 3

3-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-ethyl]pyridine(302)

To a solution of the diamine 1 (159 mg 0.75 mmol) in toluene (5 mL) isadded 2.0M trimethylaluminum in toluene (0.95 mL, 1.9 mmol), followed by301 (124 mg, 0.75 mmol), and the solution is heated at 65° C. for 6 h.The reaction is cooled to RT and quenched by the addition of sat. sodiumbicarbonate solution, followed by the addition of water and EtOAc. Theorganic layer is separated, and washed with brine, dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:7M ammonia inMeOH (95:5) gives 104 mg of the product 302. ¹H NMR (CDCl₃) δ 8.62 (s, 1H), 8.52 (d, 1 H), 7.67 (d, 1 H), 7.28 (m, 1 H), 7.05-7.00 (m, 6 H),6.8-6.7 (m, 4 H), 5.27 (bs, 2 H), 3.19 (t, 2 H), 2.82 (t, 2 H); MS: m/z328 (M⁺+1).

Example 1382-[(Tetrahydropyran-4-yl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (305)

Step 1

(Tetrahydropyran-4-ylidine)acetic acid methyl ester (303)

To a solution of tetrahydro-4H-pyran-4-one (0.462 mL, 5.0 mmol) intoluene (25 mL) is added methyl (triphenylphosphoranylidine)acetate(1.84 g, 5.5 mmol), and the solution is stirred and heated at 110° C.for 24 h. The reaction mixture is cooled to RT, diluted with Et₂O, andwashed with water, brine, then dried (MgSO₄), and filtered. The filtrateis rotary evaporated, and the residue is purified by chromatography onsilica gel; elution with EtOAc:heptane (40:60) gives 0.496 g of theproduct 303. ¹H NMR (CDCl₃) δ 5.70 (s, 1 H), 3.80-3.75 (m, 4 H), 3.70(s, 3 H), 3.00 (t, 2 H), 2.35 (t, 2 H); MS: m/z 157 (M⁺+1).

Step 2

(Tetrahydropyran-4-yl)acetic acid methyl ester (304)

To a solution of 303 (490 mg, 3.1 mmol) in 1:1 THF:MeOH (10 mL) is added10% palladium-on-carbon (74 mg), and the mixture is stirred at RT underhydrogen for 16 h. The mixture is filtered, and the filtrate isevaporated to give 481 mg of the product 304. ¹H NMR (CDCl₃) δ 4.0-3.9(m, 2 H), 3.70 (s, 3 H), 3.40 (t, 2 H), 2.25 (d, 2 H), 2.01 (m, 1 H),1.65-1.60 (m, 2 H), 1.40-1.25 (m, 2 H); MS: m/z 159 (M⁺+1).

Step 3

2-[(Tetrahydropyran-4-yl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (305)

To a solution of the diamine 1 (584 mg 2.75 mmol) in toluene (15 mL) isadded 2.0M trimethylaluminum in toluene (3.44 mL, 6.88 mmol), followedby 304 (473 mg, 3.0 mmol), and the solution is heated at 65° C. for 12h. The reaction is cooled to 20° C. and quenched by the addition of sat.sodium bicarbonate solution, and filtered. The filtrate is evaporated,and the residue is purified by reverse phase HPLC; gradient elution withacetonitrile/0.1% TFA:water/0.1% TFA (25:75-100:0) gives 178 mg of theproduct 305. ¹H NMR (DMSO-d₆) δ 10.72 (s, 2 H), 7.2-7.1 (m, 6 H),7.05-7.0 (m, 4 H), 5.80 (s, 2 H), 3.95-3.90 (m, 2 H), 3.36 (t, 2 H),2.74 (d, 2 H), 2.15 (m, 1 H), 1.75-1.70 (m, 2 H), 1.45-1.30 (m, 2 H);MS: m/z 321 (M⁺+1).

Example 1392-[(cis-4,5-Diphenyl-4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-ethyl]pyridineditrifluoroacetate (306)

To a solution of the diamine 16 (170 mg 0.75 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.980 mL, 1.95 mmol), followedby 3-(pyridin-2-yl)-propionic acid methyl ester (298) (124 mg, 0.75mmol), and the solution is heated at 90° C. for 12 h. The reaction iscooled to 20° C. and quenched by the addition of sat. sodium bicarbonatesolution, followed by the addition of water and EtOAc. The organic layeris separated, washed with brine, dried (MgSO₄), and filtered. Thefiltrate is evaporated, and the residue is purified by reverse phaseHPLC; gradient elution with acetonitrile/0.1% TFA:water/0.1% TFA(20:80-100:0) gives 55 mg of the product 306. ¹H NMR (DMSO-d₆) δ 10.84(s, 1 H), 10.67 (s, 1 H), 8.65 (m, 1 H), 7.88 (t, 1 H), 7.46 (d, 1 H),7.40 (m, 1 H), 7.1-7.0 (m, 5 H), 6.93-6.90 (m, 2 H), 6.85-6.80 (m, 2 H),5.26 (s, 1 H), 3.40 (t, 2 H), 3.26 (t, 2 H), 1.88 (s, 3 H); LC/MS: 2.60min, m/z 342 (M⁺+1).

Example 140[4,5-cis-bis-(3-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-(3-fluoro-benzyl)amine(381)

A mixture of intermediate 75 (200 mg, 0.478 mmol), 3-fluorobenzylamine(0.400 mL, 3.51 mmol) is heated at 150° C. overnight. The reactionmixture is cooled to RT. The reaction mixture is diluted withdichloromethane, washed with 3M HCl, brine, and then dried (Na₂SO₄), andfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH:HOAc(100:4:1) gives 100 mg of the product 381. ¹H NMR (CDCl₃) δ 9.80-7.60(m, 2 H), 7.50-7.10 (m, 4 H), 7.10-6.85 (m, 4 H), 6.85-6.65 (m, 2 H),6.65-6.20 (m, 4 H), 4.75 (s, 1 H), 4.60 (s, 2 H), 1.90 (s, 3 H); LC/MS:2.75 min, m/z 396 (M⁺+1).

Example 141[4,5-cis-bis-(4-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-(3-fluoro-benzyl)amine(382)

A mixture of intermediate 73 (200 mg, 0.478 mmol), 3-fluorobenzylamine(0.400 mL, 3.51 mmol) is heated at 150° C. overnight. The reactionmixture is cooled to RT. The reaction mixture is diluted withdichloromethane, washed with 3M HCl, and brine. The precipitate thatformed during drying is filtered to give 46 mg of the product 382. ¹HNMR (DMSO-d₆) δ 9.20 (m, 2 H), 7.60-7.40 (m, 1 H), 7.40-7.10 (m, 3 H),7.10-6.80 (m, 8 H), 5.15 (s, 1 H), 4.60 (s, 2 H), 1.95 (s, 3 H); LC/MS:2.79 min, m/z 396 (M⁺+1).

Example 1422-[(Phenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole (383)

To a solution of the diamine 1 (212 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution of phenoxyacetonitrile (133 mg, 1.0 mmol) in toluene (1 mL).The solution is heated at 60° C. for 2 h, then cooled to RT. Thereaction mixture is quenched with sat. sodium bicarbonate solution (2mL) and EtOAc is added, and the solution filtered. The filtrate isevaporated, and the residue purified by chromatography on silica gel;elution with dichloromethane:MeOH (9:1) gives 119 mg of the product 383.¹H NMR (CDCl₃) δ 7.37 (t, 2H), 7.1-6.9 (m, 9H), 6.88 (bs, 4H), 5.4 (bd,2H), 5.01 (bs, 2H); MS: m/z 329 (M⁺+1).

Example 1432-[(2-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(385)

Step 1.

(2-Fluorophenoxy)acetonitrile (384)

To a solution of 2-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) isadded potassium carbonate (828 mg, 6.0 mmol) followed bychloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture isstirred and heated at 50° C. for 14 h. The reaction mixture is cooled toRT, diluted with EtOAc, and washed with water, brine, then dried(MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on silica gel; elution with dichloromethanegives 736 mg of the product 384.

Step 2.

2-[(2-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(385)

To a solution of the diamine 1 (212 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution of 384 (151 mg, 1.0 mmol) in toluene (1 mL). The solution isheated at 60° C. for 2 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (2 mL) and EtOAc isadded, and the solution filtered. The filtrate is evaporated, and theresidue purified by chromatography on silica gel; elution withdichloromethane:MeOH (9:1) gives 59 mg of the product 385. ¹H NMR(CDCl₃) δ 7.40-7.25 (m, 1H), 7.24-7.11 (m, 3H), 7.00 (m, 6H), 6.88 (m,4H), 5.37 (bs, 2H), 5.06 (bs, 211); MS: m/z 347 (M⁺+1).

Example 1442-[(3-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (387)

Step 1.

3-Fluorophenoxyacetonitrile (386)

To a solution of 3-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) isadded potassium carbonate (828 mg, 6.0 mmol) followed bychloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture isstirred and heated at 50° C. for 14 h. The reaction mixture is cooled toRT, diluted with EtOAc, and washed with water, brine, then dried(MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on silica gel; elution with dichloromethanegives 712 mg of the product 386.

Step 2.

2-[(3-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (387)

To a solution of the diamine 1 (212 mg, 1.0 mmol) in toluene (6 μL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution 386 (151 mg, 1.0 mmol) in toluene (1 mL). The solution isheated at 60° C. for 2 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (2 mL) and EtOAc isadded, and the solution filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/1% TFA (30:70-100:0) gives 63mg of the product 387. ¹H NMR (CDCl₃) δ 7.31 (q, 1H), 7.7.1-7.0 (m, 6H),7.9-7.7 (m, 7H), 5.59 (s, 2H), 5.42 (s, 2H); MS: m/z 347 (M⁺+1).

Example 1452-[(4-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (389)

Step 1.

(4-Fluorophenoxy)acetonitrile (388)

To a solution of 4-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) isadded potassium carbonate (828 mg, 6.0 mmol) followed bychloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture isstirred and heated at 50° C. for 14 h. The reaction mixture is cooled toRT, diluted with EtOAc, and washed with water, brine, then dried(MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on silica gel; elution with dichloromethanegives 721 mg of the product 388.

Step 2.

2-[(4-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (389)

To a solution of the diamine 1 (212 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution 388 (151 mg, 1.0 mmol) in toluene (1 mL). The solution isheated at 60° C. for 2 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (2 mL) and EtOAc isadded, and the solution filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/1% TFA (30:70-100:0) gives 48mg of the product 389. ¹H NMR (CDCl₃) δ 7.1-6.9 (m, 10H), 6.82 (m, 4H),5.59 (bs, 2H), 5.42 (bs, 2H); MS: m/z 347 (M⁺+1).

Example 1462-[(Benzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole (391)

Step 1.

Benzyloxyacetic acid ethyl ester (390)

To a solution of benzyl alcohol (1.04 mL, 10.0 mmol) in dichloromethane(30 mL) is added rhodium (II) acetate dimer (40 mg) followed by ethyldiazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RTfor 20 min. The reaction mixture is rotary evaporated, and the residueis vacuum distilled at 110° C. to give 1.81 g of the product 390. ¹H NMR(CDCl₃) δ 7.4-7.26 (m, 5H), 4.65 (s, 2H), 4.23 (q, 2H), 4.10 (s, 2H),1.30 (t, 3H).

Step 2.

2-[(Benzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole (391)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by390 (100 mg, 0.5 mmol), and the solution is heated at 60° C. for 6 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.5 mL) and EtOAc is added, and the solution isdried (MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on silica gel; elution withdichloromethane:MeOH (92:8) gives 49 mg of the product 391. ¹H NMR(CDCl₃) δ 7.4-7.26 (m, 5H), 7.01 (m, 6H), 6.92 (m, 4H), 5.31 (bs, 2H),4.70 (s, 2H), 4.48 (s, 2H); MS: m/z 343 (M⁺).

Example 1472-[(3-Fluorobenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (393)

Step 1.

3-Fluorobenzyloxyacetic acid ethyl ester (392)

To a solution of 3-fluorobenzyl alcohol (1.12 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at RT for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 150° C. to give 1.88 g of the product392. ¹H NMR (CDCl₃) δ 7.30 (m, 1H), 7.12 (m, 2H), 6.99 (dt, 1H), 4.63(s, 2H), 4.28 (q, 2H), 4.11 (s, 2H), 1.30 (t, 3H); MS: m/z 213 (M⁺+1).

Step 2.

2-[(3-Fluorobenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (393) (Scheme 11, Method b)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by392 (106 mg, 0.53 mmol), and the solution is heated at 60° C. for 6 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.2 mL) and EtOAc is added, and the solutionfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH (94:6)followed by treatment with hydrogen chloride in Et₂O gives 17 mg of theproduct 393. ¹H NMR (CDCl₃) δ 10.3 (bs, 2H), 7.37 (m, 1H), 7.26-7.0 (m,9H), 6.88 (m, 4H), 5.68 (s, 2H), 5.17 (s, 2H), 4.73 (s, 2H)

Example 1482-[(3-Trifluoromethylbenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (395)

Step 1.

(3-Trifluoromethylbenzyloxy)acetic acid ethyl ester (394)

To a solution of 3-trifluoromethylbenzyl alcohol (1.62 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at RT for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 150° C. to give 2.31 g of the product394. ¹H NMR (CDCl₃) δ 7.65 (bs, 1H), 7.57 (m, 2H), 7.48 (t, 1H), 4.69(s, 2H), 4.24 (q, 2H), 4.14 (s, 2H), 1.30 (t, 3H); MS: m/z 263 (M⁺).

Step 2.

2-[(3-Trifluoromethylbenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (395)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by394 (131 mg, 0.53 mmol), and the solution is heated at 60° C. for 6 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.2 mL) and EtOAc is added, and the solutionfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH (94:6)followed by treatment with hydrogen chloride in Et₂O gives 14 mg of theproduct 395. ¹H NMR (DMSO-d₆) δ 10.90 (s, 2H), 7.85 (bs, 1H), 7.81-7.64(m, 31H), 7.15-7.0 (m, 10H), 5.81 (s, 2H), 4.87 (s, 4H); MS: m/z 411(M⁺+1).

Example 1492-[(3-Methylbenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (397)

Step 1.

(3-Methylbenzyloxy)acetic acid ethyl ester (396)

To a solution of 3-methylbenzyl alcohol (1.08 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at RT for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 150° C. to give 1.91 g of the product396. ¹H NMR (CDCl₃) δ 7.3-7.1 (m, 4H), 4.60 (s, 2H), 4.23 (q, 2H), 4.09(s, 2H), 2.36 (s, 3H), 1.29 (t, 311); MS: m/z 209 (M⁺+1).

Step 2.

2-[(3-Methylbenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (397)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by396 (194 mg, 0.53 mmol), and the solution is heated at 60° C. for 6 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.2 mL) and EtOAc is added, and the solutionfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH (94:6)followed by treatment with hydrogen chloride in Et₂O gives 40 mg of theproduct 397. ¹H NMR (DMSO-d₆) δ 10.91 (s, 2H), 7.34-6.99 (m, 14H), 5.79(s, 2H), 4.79 (s, 21H), 4.72 (s, 2H), 2.34 (s, 3H); MS: m/z 357 (M⁺+1).

Example 1502-[(3-Methoxybenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (399)

Step 1.

(3-Methoxybenzyloxy)acetic acid ethyl ester (398)

To a solution of 3-methoxybenzyl alcohol (1.24 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at RT for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 150° C. to give 2.00 g of the product398. ¹H NMR (CDCl₃) δ 7.26 (t, 1H), 6.93 (m, 2H), 6.85 (m, 1H), 4.62 (s,2H), 4.23 (q, 2H), 4.09 (s, 2H), 3.81 (s, 3H), 1.29 (t, 3H); MS: m/z 224(M⁺+1).

Step 2.

2-[(3-Methoxybenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (399)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by398 (210 mg, 0.53 mmol), and the solution is heated at 60° C. for 6 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.2 mL) and EtOAc is added, and the solutionfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH (94:6)followed by treatment with hydrogen chloride in Et₂O gives 34 mg of theproduct 399. ¹H NMR (DMSO-d₆) δ 10.87 (s, 2H), 7.34 (t, 1H), 7.13-6.96(m, 12H), 6.92 (m, 1H), 5.79 (s, 2H), 4.79 (s, 2H), 4.74 (s, 2H), 3.78(s, 3H); MS: m/z 373 (M⁺+1).

Example 1512-[(Phenylsulfanyl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (401)

Step 1

(Phenylthio)acetic acid ethyl ester (400)

To a solution of thiophenol (1 mL, 9.7 mmol) in DMF (20 mL) is addedpotassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL,10.6 mmol), and the mixture is stirred at RT for 25 min. Et₂O is added,and the mixture is washed with water, brine, then dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is vacuumdistilled (130-140° C.) to give 1.71 g of the product 400. ¹H NMR(CDCl₃) δ 7.41 (d, 2H), 7.33-7.2 (m, 4H), 4.16 (q, 2H), 3.63 (s, 2H),1.22 (t, 3H); MS: m/z 196 (M⁺+1).

Step 2

2-[(Phenylsulfanyl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (401)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (1.5 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.3 mmol) followed by400 (98 mg, 0.50 mmol), and the solution is heated at 80° C. for 2.5 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.6 mL) and EtOAc:dichloromethane is added, andthe solution filtered. The filtrate is evaporated, and the residuepurified by chromatography on reversed phase silica gel; elution withacetonitrile:water/0.1% TFA gives 96 mg of the product 401. ¹H NMR(CDCl₃) δ 10.8 (bs, 2H), 7.60 (m, 2H), 7.45-7.3 (m, 3H), 7.05-6.9 (m,6H), 6.58 (m, 4H), 5.52 (s, 2H), 4.50 (s, 2H); LC/MS: 3.24 min, nm/z 345(M⁺+1).

Example 1522-[(Benzylsulfanyl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (403)

Step 1

(Benzylsulfanyl)acetic acid ethyl ester (402)

To a solution of benzyl mercaptan (1.18 mL, 10.0 mmol) in DMF (20 mL) isadded potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate(1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et₂Ois added, and the mixture is washed with water, brine, then dried(MgSO₄), and filtered. The filtrate is evaporated, and the residue isvacuum distilled (130-140° C.) to give 1.05 g of the product 402.

Step 2

2-[(Benzylsulfanyl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (403)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.3 mmol) followed by402 (105 mg, 0.50 mmol), and the solution is heated at 80° C. for 2.5 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.6 mL) and EtOAc:dichloromethane is added, andthe solution filtered. The filtrate is evaporated, and the residuepurified by chromatography on reversed phase silica gel; elution withacetonitrile:water/0.1% TFA gives 96 mg of the product 403. ¹H NMR(CDCl₃) δ 10.8 (bs, 2H), 7.44-7.3 (m, 5H), 7.05 (m, 6H), 6.73 (m, 4H),5.23 (s, 2H), 4.08 (s, 2H), 3.98 (s, 2H); LC/MS: 3.35 min, m/z 359(M⁺+1).

Example 1532-[(Methoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (404)

To a solution of the diamine 1 (159 mg, 0.75 mmol) in toluene (2.5 mL)is added 2.0M trimethylaluminum in toluene (0.980 mL, 1.96 mmol)followed by methoxyacetic acid methyl ester (0.74 mL, 0.75 mmol), andthe solution is heated at 90° C. for 3 h, then cooled to rt. Thereaction mixture is quenched with sat. sodium bicarbonate solution (1.5mL) and EtOAc is added, and the mixture is dried (MgSO₄), and filtered.The filtrate is evaporated, and the residue purified by chromatographyon reversed phase silica gel; elution with acetonitrile/0.1%TFA:water/0.1% TFA gives 63 mg of the product 404. ¹H NMR (DMSO-d₆) δ10.85 (s, 1 H), 7.1-7.0 (m, 10 H), 5.80 (s, 2 H), 4.71 (s, 2 H), 3.51(s, 3 H); LC/MS: 2.80 min, m/z 267 (M⁺+1).

Example 1542-[(Isopropoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (406)

Step 1

Isopropoxyacetic acid ethyl ester (405)

To a solution of 2-propanol (0.776 mL, 10.0 mmol) in dichloromethane (33mL) is added rhodium (II) acetate dimer (22 mg) followed by ethyldiazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at RTfor 30 min. The reaction mixture is filtered through Celite, and thefiltrate is evaporated and the residue is vacuum distilled at 150° C. togive 750 mg of the product 405. ¹H NMR (CDCl₃) δ 4.21 (q, 2 H), 4.06 (s,2 H), 3.73 (m, 1 H), 1.29 (t, 3 H), 1.22 (s, 3 H), 1.19 (s, 3 H); MS:m/z 147 (M⁺+1).

Step 2

2-[(Isopropoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (406)

To a solution of the diamine 1 (159 mg, 0.75 mmol) in toluene (2.5 mL)is added 2.0M trimethylaluminum in toluene (0.980 mL, 1.96 mmol)followed by 405 (110 mg, 0.75 mmol), and the solution is heated at 90°C. for 3 h, then cooled to rt. The reaction mixture is quenched withsat. sodium bicarbonate solution (1.5 mL) and EtOAc is added, and themixture is dried (MgSO₄), and filtered. The filtrate is evaporated, andthe residue purified by chromatography on reversed phase silica gel;elution with acetonitrile/0.1% TFA:water/0.1% TFA gives 56 mg of theproduct 406. ¹H NMR (DMSO-d₆) δ 10.73 (s, 1 H), 7.2-7.0 (m, 10 H), 5.79(s, 2 H), 4.72 (s, 2H), 3.86 (m, 1 H), 1.25 (s, 3 H), 1.23 (s, 3H);LC/MS: 3.05 min, m/z 295 (M⁺+1).

Example 1552-[(Cyclohexyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (408)

Step 1

Cyclohexyloxyacetic acid ethyl ester (407)

To a solution of cyclohexanol (1.0 g, 0.95 mmol) in dichloromethane (30mL) is added rhodium (II) acetate dimer (44 mg) followed by ethyldiazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RTfor 20 min. The reaction mixture is diluted with Et₂O, filtered throughCelite, and the filtrate is evaporated and the residue is vacuumdistilled at 150° C. to give 1.57 g of the product 407. ¹H NMR (CDCl₃) δ4.23 (q, 2H), 4.10 (s, 2H), 3.33 (m, 1H), 1.93 (m, 2H), 1.74 (m, 2H),1.54 (m, 1H), 1.4-1.1 (m, 8H)

Step 2

2-(Cyclohexyloxy)methyl-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (408)

To a solution of the diamine 1 (212 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution of 407 (186 mg, 1.0 mmol) in toluene (1 mL). The solution isheated at 60° C. for 2 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (1.5 mL) and EtOAc isadded, and the mixture is dried (MgSO₄), and filtered. The filtrate isevaporated, and the residue purified by chromatography on reversed phasesilica gel; gradient elution with acetonitrile:water/0.1% TFA(30:70-100:0) gives 54 mg of the product 408. ¹H NMR (CDCl₃) δ 7.10 (m,6H), 6.89 (m, 4H), 5.67 (s, 2H), 4.96 (s, 2H), 3.53 (m, 1H), 1.99 (m,2H), 1.76 (m, 2H), 1.57 (m, 1H), 1.2-1.05 (m, 5H); MS: m/z 335 (M⁺+1).

Example 1562-[(Tetrahydropyran-4-yloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (410)

Step 1

(Tetrahydropyran-4-yloxy)acetic acid ethyl ester (409)

To a solution of tetrahydro-4H-pyran-4-one (1.0 g, 10.0 mmol) in cold(0° C.) THF is added 1.0M lithium aluminum hydride in THF (5 mL, 5.0mmol). The reaction mixture is stirred at 0° C. for 15 min. followed bythe sequential addition of water (0.190 mL), 5M sodium hydroxide (0.190mL), and water (0.190 mL) and Et₂O. The mixture is filtered, and thefiltrate is evaporated to give tetrahydro-4H-pyran-4-ol, which isdissolved in dichloromethane (30 mL). To the solution is added rhodium(II) acetate dimer (44 mg) followed by ethyl diazoacetate (1.25 g, 11.0mmol). The reaction mixture is stirred at RT for 40 min. The reactionmixture is diluted with ethanol, filtered through Celite, and thefiltrate is evaporated and the residue is vacuum distilled at 150° C. togive 1.67 g of the product 409. ¹H NMR (CDCl₃) δ 4.21 (q, 2H), 4.11 (s,2H), 3.95 (dt, 2H), 3.59 (m, 1H), 3.42 (dt, 2H), 1.91 (m, 2H), 1.62 (m,2H), 1.28 (t, 3H); MS: m/z 189 (M⁺+1).

Step 2

2-[(Tetrahydropyran-4-yloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (410)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (4 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by asolution of 409 (95 mg, 0.5 mmol) in toluene (1 mL). The solution isheated at 70° C. for 6 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL) and EtOAc isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA (30:70-100:0) gives109 mg of the product 410. ¹H NMR (DMSO-d₆) δ 10.76 (s, 2H), 7.15-7.00(m, 10H), 5.80 (s, 2H), 4.80 (s, 2H), 3.9-3.75 (m, 3H), 3.39 (dt, 2H),1.96 (m, 2H), 1.56 (m, 2H); MS: m/z 337 (M⁺+1).

Example 1572-[(Cycloheptyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (412)

Step 1

Cycloheptyloxyacetic acid ethyl ester (411)

To a solution of cycloheptanol (0.600 mL, 5.0 mmol) in dichloromethane(15 mL) is added rhodium (II) acetate dimer (21 mg) followed by ethyldiazoacetate (0.60 g, 5.7 mmol). The reaction mixture is stirred at RTfor 10 min. The reaction mixture is rotary evaporated, and the residuedissolved in Et₂O, filtered through Celite, and the filtrate isevaporated and the residue is vacuum distilled at 150° C. to give 0.960g of the product 411. ¹H NMR (CDCl₃) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.50(m, 1H), 1.93 (m, 2H), 1.7-1.4 (m, 8H), 1.4-1.3 (m, 2H), 1.28 (t, 3H);MS: m/z 201 (M⁺+1).

Step 2

2-[(Cycloheptyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (412)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (4 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by asolution of 411 (100 mg, 0.5 mmol) in toluene (1 mL). The solution isheated at 70° C. for 6 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL) and EtOAc isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA (30:70-100:0) gives 58mg of the product 412. ¹H NMR (DMSO-d₆) δ 10.70 (s, 2H), 7.15-7.00 (m,10H), 5.79 (s, 2H), 4.70 (s, 2H), 3.73 (m, 1H), 1.94 (m, 2H), 1.95 (m,2H), 1.73-1.6 (m, 4H), 1.6-1.5 (m, 4H), 1.5-1.3 (m, 2H); MS: m/z 349(M⁺+1).

Example 1582-[(Cyclooctyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (414)

Step 1

Cyclooctyloxyacetic acid ethyl ester (413)

To a solution of cyclooctanol (640 mg, 4.9 mmol) in dichloromethane (15mL) is added rhodium (II) acetate dimer (21 mg) followed by ethyldiazoacetate (0.60 g, 5.7 mmol). The reaction mixture is stirred at RTfor 10 min. The reaction mixture is rotary evaporated, and the residuedissolved in Et₂O, filtered through Celite, and the filtrate isevaporated and the residue is vacuum distilled at 150° C. to give 397 mgof the product 413. ¹H NMR (CDCl₃) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.50(m, 1H), 1.93 (m, 2H), 1.7-1.4 (m, 8H), 1.4-1.3 (m, 2H), 1.28 (t, 3H);MS: m/z 215 (M⁺+1).

Step 2

2-[(Cyclooctyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (414)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (4 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by asolution of 413 (107 mg, 0.5 mmol) in toluene (1 mL). The solution isheated at 70° C. for 6 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL) and EtOAc isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA (30:70-100:0) gives 53mg of the product 414. ¹H NMR (CDCl₃) δ 7.15-7.0 (m, 6H), 6.88 (m, 4H),5.67 (s, 2H), 4.93 (s, 2H), 3.71 (m, m, 1H), 1.95-1.8 (m, 2H), 1.8-1.6(m, 4H), 1.6-1.4 (m, 8H); MS: m/z 363 (M⁺+1).

Example 1592-(Cyclohexylmethoxymethyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(420)

Step 1

(Cyclohexylmethoxy)acetic acid ethyl ester (419)

To a solution of cyclohexylmethanol (1.23 mL, 10.0 mmol) indichloromethane (30 mL) is added rhodium (II) acetate dimer (11 mg)followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reactionmixture is stirred at RT for 30 min. To the reaction mixture is addedMeOH, and the reaction mixture is rotary evaporated, and the residuedissolved in Et₂O, filtered through Celite, and the filtrate isevaporated and the residue is vacuum distilled at to give 2.02 g of theproduct 419. ¹H NMR (CDCl₃) δ 4.22 (q, 2 H), 4.05 (s, 2 H), 3.33 (d, 2H), 1.8-1.5 (m, 7 H), 1.4-1.1 (m, 5 H), 1.1-0.9 (m, 2 H); MS: m/z 200(M⁺+1).

Step 2

2-(Cyclohexylmethoxymethyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(420)

To a solution of the diamine 1 (276 mg, 1.3 mmol) in toluene (4 mL) isadded 2.0M trimethylaluminum in toluene (1.62 mL, 3.24 mmol) followed bya solution of 419 (260 mg, 1.3 mmol) in toluene (1 mL). The solution isheated at 65° C. for 4 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (3 mL) and EtOAc isadded, and the mixture is filtered, dried (MgSO₄), and filtered. Thefiltrate is evaporated, and the residue purified by chromatography onsilica gel; elution with EtOAc:MeOH:heptane (65:5:30) gives 31 mg of theproduct 420. ¹H NMR (DMSO-d₆) δ 7.1 (bs, 1 H), 7.0-6.9 (m, 10 H), 5.22(bs, 2 H), 4.21 (s, 2 H), 3.41-3.39 (d, 2 H), 1.8-1.6 (m, 5 H), 1.2-1.1(m, 4 H), 1.0-0.9 (m, 2 H); LC/MS: 3.50 min, m/z 349 (M⁺+1).

Example 160[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]benzylamineditrifluoroacetate (422)

Step 1

(Benzylamino)acetic acid ethyl ester (421)

To a solution of ethyl bromoacetate (2.22 mL, 20.0 mmol) in 1,4-dioxane(40 mL) is added N,N-diisopropylethylamine (7.0 mL, 40.0 mol) andbenzylamine (3.3 mL, 30.0 mmol), and the mixture is heated at 90° C. for3 h. The reaction mixture is cooled to RT, dichloromethane is added, andthe solution is washed with water, brine, then dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is residuepurified by chromatography on silica gel; elution withEtOAc:MeOH:heptane (35:5:60) gives 2.9 g of the product 421. ¹H NMR(CDCl₃) δ 7.4-7.3 (m, 6 H), 4.19 (q, 2 H), 3.80 (s, 2 H), 3.40 (s, 2 H),1.25 (t, 3 H); MS: m/z 194 (M⁺+1).

Step 2

[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]benzylamineditrifluoroacetate (422)

To a solution of the diamine 1 (637 mg, 3.0 mmol) in toluene (11 mL) isadded 2.0M trimethylaluminum in toluene (3.9 mL, 7.8 mmol) followed by asolution of 421 (580 mg, 3.0 mmol) in toluene (2 mL). The solution isheated at 90° C. for 6.5 h, then cooled to RT. The reaction is quenchedwith sat. sodium bicarbonate solution (4 mL) and EtOAc:dichloromethaneis added, and the mixture is filtered, and the filtrate is dried(MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on reversed phase silica gel; gradientelution with acetonitrile/0.1% TFA:water/0.1% TFA (30:70-100:0) gives166 mg of the product 422. ¹H NMR (DMSO-d₆) δ 10.61 (bs, 1 H), 7.5-7.3(m, 5 H), 7.1-7.0 (m, 10 H), 5.75 (s, 2H), 4.04 (s, 2H), 4.00 (s, 2H);LC/MS: 2.95 min, m/z 342 (M⁺+1).

Example 1612-[(2-Phenethyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(424)

Step 1

(2-Phenethyloxy)acetic acid ethyl ester (423)

To a solution of 2-phenethyl alcohol (0.597 mL, 5.0 mmol) indichloromethane (15 mL) is added rhodium (II) acetate dimer (6 mg)followed by ethyl diazoacetate (0.526 mL, 5.0 mmol). The reactionmixture is stirred at RT for 30 min. To the reaction mixture is addedMeOH, and the reaction mixture is rotary evaporated, and the residuepurified by chromatography on silica gel; elution with EtOAc:heptane(20:80) gives 713 mg of the product 423. ¹H NMR (CDCl₃) δ 7.3-7.2 (m, 5H), 4.20 (q, 2 H), 4.09 (s, 2 H), 3.75 (t, 2 H), 2.95 (t, 2 H), 1.29 (t,3 H); MS: m/z 209 (M⁺+1).

Step 2

2-[(2-Phenethyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole(424)

To a solution of the diamine 1 (318 mg, 1.5 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (2.25 mL, 4.5 mmol) followed bya solution of 423 (312 mg, 1.5 mmol) in toluene (2 mL). The solution isheated at 65° C. for 6 h, then cooled to RT. The reaction is quenchedwith sat. sodium bicarbonate solution (3 mL) and EtOAc: is added, andthe mixture is filtered, and the filtrate is dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with EtOAC:MeOH:heptane (70:10:20)gives 84 mg of the product 424. ¹H NMR (DMSO-d₆) δ 7.27 (d, 4 H),7.2-7.1 (m, 1 H), 7.0-6.9 (m, 11 H), 5.19 (bs, 2 H), 4.24 (s, 2 H), 3.78(t, 2 H), 2.89 (t, 2 H); LC/MS: 3.33 min, m/z 357 (M⁺+1).

Example 1621-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-pyridin-2-one(426)

Step 1

(2-Oxo-2H-pyridin-1-yl)acetic acid ethyl ester (425)

To a suspension of 60% sodium hydride dispersion in mineral oil (220 mg,5.5 mmol) in cold (0° C.) THF is added 2-pyridone (475 mg, 5.0 mmol) inTHF (4 mL) and DMPU (2 mL) followed by ethyl bromoacetate (0.556 mL, 5.0mmol), and the reaction is stirred at RT for 1 h. The reaction isquenched with water, and extracted with EtOAc. The organic layer isseparated, evaporated, and the residue purified by chromatography onsilica gel; elution with EtOAC:dichloromethane:heptane (50:30:20) gives690 mg of the product 425. ¹H NMR (CDCl₃) δ 7.35 (m, 1H), 7.21 (d, 1H),6.57 (d, 1H), 6.19 (t, 1H), 4.62 (s, 2H), 4.23 (q, 2H), 1.28 (t, 3H);MS: m/z 182 (M⁺+1).

Step 2

1-[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-pyridin-2-one(426)

To a solution of the diamine 1 (106 mg, 0.5 mmol) in toluene (4 mL) isadded 2.0M trimethylaluminum in toluene (0.6 mL, 1.2 mmol) followed by asolution of 425 (90 mg, 0.5 mmol) in toluene (1 mL). The solution isheated at 70° C. for 6 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL) and EtOAc isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on silica gel; elution withdichloromethane:MeOH (95:5) gives 23 mg of the product 426. ¹H NMR(DMSO-d₆) δ 10.97 (s, 2H), 7.84 (dd, 1H) 7.58 (dt, 1H), 7.15-7.0 (m,10H), 6.60 (d, 1H), 6.39 (t, 1H), 5.79 (s, 2H), 5.25 (s, 2H); MS: m/z330 (M⁺+1).

Example 1632-[(2-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole(427)

To a solution of the diamine 5 (248 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution of (2-fluorophenoxy)acetonitrile (384) (151 mg, 1.0 mmol) intoluene (1 mL). The solution is heated at 90° C. overnight, then cooledto RT. The reaction mixture is quenched with sat. sodium bicarbonatesolution (2 mL) and EtOAc and water are added, and the organic solutionis separated, washed with brine, dried (MgSO₄), and filtered. Thefiltrate is evaporated, and the residue purified by chromatography onsilica gel; gradient elution with EtOAc:heptane (1:5-1:1) followed bytrituration with Et₂O gives 17 mg of the product 427. LC/MS: 1.45 min,m/z 383 (M⁺+1).

Example 1642-[(3-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole(428)

To a solution of the diamine 5 (248 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution of 3-fluorophenoxyacetonitrile (386) (151 mg, 1.0 mmol) intoluene (1 mL). The solution is heated at 70° C. overnight, then cooledto RT. The reaction mixture is quenched with sat. sodium bicarbonatesolution (2 mL) and EtOAc and water are added, and the organic solutionis separated, washed with brine, dried (MgSO₄), and filtered. Thefiltrate is evaporated, and the residue triturated with heptane:Et₂O togive 44 mg of the product 428. LC/MS: 1.46 min, m/z 383 (M⁺+1).

Example 1652-[(4-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole(429)

To a solution of the diamine 5 (248 mg, 1.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (1.0 mL, 2.0 mmol) followed by asolution of (4-fluorophenoxy)acetonitrile (388) (151 mg, 1.0 mmol) intoluene (1 mL). The solution is heated at 60° C. for 2.5 h, then cooledto RT. The reaction mixture is quenched with sat. sodium bicarbonatesolution (2 mL) and EtOAc and water are added, and the organic solutionis separated, washed with brine, dried (MgSO₄), and filtered. Thefiltrate is evaporated, and the residue crystallized from Et₂O to give70 mg of the product 429. LC/MS: 1.44 min, m/z 383 (M⁺+1).

Example 1662-[(Phenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (431)

Step 1

Phenoxyacetic acid ethyl ester (430)

To a solution of phenol (1.88 g, 20.0 mmol) in DMF (40 mL) is addedpotassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL,21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixtureis cooled to RT, Et₂O is added, and the mixture is washed with water,brine, then dried (MgSO₄), and filtered. The filtrate is evaporated, andthe residue is vacuum distilled to give 3.39 g of the product 430.

Step 2

2-[(Phenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (431)

To a solution of the diamine 16 (226 mg, 1.0 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (1.3 mL, 2.6 mmol) followed by asolution of phenoxyacetic acid ethyl ester (430) (186 mg, 1.0 mmol) intoluene (1 mL). The solution is heated at 90° C. for 2 h, then cooled toRT. The reaction mixture is quenched with sat. sodium bicarbonatesolution (0.5 mL), EtOAc is added, and the mixture is filtered. Thefiltrate is evaporated, and the residue is purified by chromatography onreversed phase silica gel; gradient elution with acetonitrile:water/0.1%TFA (30:70-100:0) gives 233 mg of the product 431. ¹H NMR (CDCl₃) δ 7.35(t, 2H), 7.11-7.0 (m, 9H), 6.86 (m, 2H, 6.77 (d, 2H), 5.50 (s, 2H), 5.15(s, 1H), 1.98 (s, 3H); LC/MS: 3.26 min, m/z 343 (M⁺+1).

Example 1672-[(3-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (433)

Step 1

3-Fluorophenoxyacetic acid ethyl ester (432)

To a solution of 3-fluorophenol (2.24 g, 20.0 mmol) in DMF (40 mL) isadded potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate(2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. Themixture is cooled to RT, Et₂O is added, and the mixture is washed withwater, brine, then dried (MgSO₄), and filtered. The filtrate isevaporated, and the residue is vacuum distilled to give 3.2 g of theproduct 432.

Step 2

2-[(3-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (433)

To a solution of the diamine 16 (113 mg, 0.5 mmol) in toluene (1.5 mL)is added 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followedby a solution of 432 (106 mg, 0.5 mmol) in toluene (1 mL). The solutionis heated at 90° C. for 2 h, then cooled to RT. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.4 mL), EtOAc is added,and the mixture is filtered. The filtrate is evaporated, and the residueis purified by chromatography on reversed phase silica gel; gradientelution with acetonitrile:water/0.1% TFA (30:70-100:0) gives 183 mg ofthe product 433. ¹H NMR (CDCl₃) δ 7.27 (t, 1H), 7.1-6.9 (m, 6H),6.82-6.72 (m, 7H), 5.31 (s, 2H), 5.12 (s, 1H), 1.93 (s, 3H); LC/MS: 3.32min, m/z 361 (M⁺+1).

Example 1682-(Cyclohexylmethoxy)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (434)

To a solution of the diamine 16 (113 mg, 0.5 mmol) in toluene (1.5 mL)is added 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followedby a solution of cyclohexyloxyacetic acid ethyl ester (407) (100 mg, 0.5mmol) in toluene (1 mL). The solution is heated at 90° C. for 2 h, thencooled to RT. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL), EtOAc is added, and the mixture isfiltered. The filtrate is evaporated, and the residue is purified bychromatography on reversed phase silica gel; gradient elution withacetonitrile:water/0.1% TFA (30:70-100:0) gives 163 mg of the product434. ¹H NMR (CDCl₃) δ 11.0 (bs, 1H), 9.6 (bs, 1H), 7.13-7.05 (m, 6H),6.87 (m, 2H), 6.83 (m, 2H), 5.20 (s, 1H), 4.95 (d, 1H), 4.93 (d, 1H),3.50 (m, 1H), 2.03 (s, 3H), 2.0 (m, 2H), 1.76 (m, 2H), 1.59 (m, 1H),1.4-1.1 (m, 5H); LC/MS: 3.42 min, m/z 349 (M⁺+1).

Example 169 Mixture of2-[(3-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-1,4-dimethyl-4,5-dihydro-1H-imidazoletrifluoroacetate and2-[(3-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-1,5-dimethyl-4,5-dihydro-1H-imidazoletrifluoroacetate (435)

To a solution of2-[(3-fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazole(433) (104 mg, 0.29 mmol) in cold (0° C.) DMF (1 mL) is added sodiumhydride (60% dispersion in mineral oil) (12 mg, 0.3 mmol), and thenmethyl iodide (0.018 mL, 0.29 mmol). The reaction mixture is stirred for1 h, quenched with ammonium chloride solution, diluted with EtOAc, andthe organic layer is separated, washed with water, brine, then dried(MgSO₄), and filtered. The filtrate is evaporated, and the residue ispurified by chromatography on reversed phase silica gel; gradientelution with acetonitrile:water/0.1% TFA (35:65-100:0) gives 92 mg ofthe product 435 as a 3:1 mixture of 1-methyl and 3-methyl diastereomers.

Example 1702-[2-(2-Chlorophenoxy)ethoxymethyl]-1-[(cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (437)

Step 1

2-[2-(2-Chlorophenoxy)ethoxy]acetic acid ethyl ester (436)

To a solution of 2-(2-chlorophenoxy)ethanol (1.73 mL, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg)followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reactionmixture is stirred at rt for 20 min. To the reaction mixture is addedMeOH followed by rotary evaporated, and the residue is purified bychromatography on silica gel; elution with EtOAc:heptane (25:75) gives1.36 g of the product 436. ¹H NMR (CDCl₃) δ 7.35 (d, 1 H), 7.19 (d, 1H), 6.95-6.90 (m, 2 H), 4.30 (s, 2 H), 4.25-4.15 (m, 4 H), 4.0 (t, 2 H),1.2 (t, 3 H); MS: m/z 259 (M⁺+1).

Step 2

2-[2-(2-Chlorophenoxy)ethoxymethyl]-1-[(cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (437) (Scheme 11, Method b)

To a solution of the diamine 16 (113 mg, 0.5 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followed bya solution of 436 (129 mg, 0.5 mmol) in toluene (1 mL). The solution isheated at 90° C. for 9 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.4 mL), EtOAc is added,and the mixture is dried (MgSO₄), and filtered. The filtrate isevaporated, and the residue is purified by chromatography on reversedphase silica gel; gradient elution with acetonitrile/0.1% TFA:water/0.1%TFA (40:60-85:15) gives 32 mg of the product 437. ¹H NMR (DMSO-d₆) δ11.02 (s, 1 H), 10.81 (s, 1 H), 7.46 (d, 1 H), 7.34 (m, 1 H), 7.03 (m,11 H), 5.34 (s, 1 H), 4.97 (s, 2 H), 4.34 (m, 2 H), 4.10 (m, 2 H), 1.93(s, 3 H); LC/MS: 3.29 min, m/z 421 (M⁺+1).

Example 1712-[(2,3-Dihydrobenzo-1,4-dioxan-2-yl)methoxymethyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (439)

Step 1

(2,3-Dihydrobenzo-1,4-dioxan-2-yl)acetic acid ethyl ester (438)

To a solution of 2-hydroxymethyl-1,4-benzodioxan (1.66 mL, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg)followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reactionmixture is stirred at rt for 20 min. To the reaction mixture is addedMeOH, and the reaction mixture is rotary evaporated, and the residuepurified by chromatography on silica gel; elution with EtOAc:heptane(25:75) gives 0.242 g of the product 438. ¹H NMR (CDCl₃) δ 6.9-6.8 (m, 4H), 4.4-4.1 (m, 7 H), 3.9-3.8 (m, 2 H), 1.30 (t, 3 H); MS: m/z 253(M⁺+1).

Step 2

2-[(2,3-Dihydrobenzo-1,4-dioxan-2-yl)methoxymethyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (439)

To a solution of the diamine 16 (113 mg, 0.5 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followed bya solution of 438 (126 mg, 0.5 mmol) in toluene (1 mL). The solution isheated at 90° C. for 9 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.4 mL), EtOAc is added,and the mixture is dried (MgSO₄), and filtered. The filtrate isevaporated, and the residue is purified by chromatography on reversedphase silica gel; gradient elution with acetonitrile/0.1% TFA:water/0.1%TFA (40:60-85:15) gives 36 mg of the product 439. ¹H NMR (DMSO-d₆) δ11.00 (s, 1H), 10.80 (s, 1 H), 7.1-7.0 (m, 10 H), 6.9-6.8 (m, 4 H), 5.35(m, 1 H), 4.89 (s, 2 H), 4.5-3.7 (m, 5 H), 1.94 (s, 3 H); LC/MS: 2.82min, m/z 415 (M⁺+1).

Example 1722-[[(Phenoxy)ethoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (441)

Step 1

(2-Phenoxy)ethoxyacetic acid ethyl ester (440)

To a solution of 2-phenoxyethan-1-ol (1.5 mL, 12.7 mmol) indichloromethane (50 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (1.1 mL, 10.5 mmol). The reaction mixtureis stirred at rt overnight. The reaction mixture is diluted withheptane, and filtered. The filtrate is evaporated, and the residuevacuum distilled to give 1.95 g of the product 440. ¹H NMR (CDCl₃) δ7.40-7.25 (m, 2 H), 7.10-6.90 (m, 3 H), 4.30-4.15 (m, 5 H), 4.15-4.05(m, 1 H), 4.05-3.90 (s, 2 H), 1.28 (t, 3 H)

Step 2

2-[[(Phenoxy)ethoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (441)

To a solution of the diamine 16 (452 mg, 2.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (2.5 mL, 5.0 mmol) followed by asolution of 440 (448 mg, 2.0 mmol) in toluene (1 mL). The solution isheated at 110° C. for 2 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.4 mL), EtOAc is added,and the mixture is filtered, washed with brine, then dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:MeOH:NH₄OH(95:5:1) followed by treatment with hydrogen chloride in Et₂O gives 151mg of the product 441. ¹H NMR (CDCl₃) δ 7.30-7.10 (m, 4 H), 7.10-6.70(m, 12 H), 4.81 (bs, 1 H), 4.65-4.45 (m, 2 H), 4.30-4.10 (m, 2 H),4.10-3.90 (m, 2 H), 1.90 (s, 3 H); MS: m/z 387 (M⁺+1).

Example 1732-[(Benzylsulfanyl)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole(442)

To a solution of the diamine 16 (170 mg, 0.75 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.980 mL, 1.95 mmol) followedby a solution of (benzylsulfanyl)acetic acid ethyl ester (402) (158 mg,0.75 mmol) in toluene (1 mL). The solution is heated at 90° C. for 2 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL), EtOAc is added, and the mixture isfiltered, and the filtrate is dried (MgSO₄), and filtered. The filtrateis evaporated, and the residue is purified by chromatography on silicagel; elution with dichloromethane:MeOH (95:5) gives 20 mg of the product442. ¹H NMR (DMSO-d₆) δ 7.4-7.3 (m, 5 H), 7.0-6.9 (m, 10 H), 4.77 (bs, 1H), 3.91 (s, 2 H), 3.50 (s, 2 H), 1.79 (s, 3 H); LC/MS: 3.32 min, m/z373 (M⁺+1).

Example 1742-[(Cyclopentyloxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (445)

Step 1

Cyclopentyloxyacetic acid ethyl ester (444)

To a solution of cyclopentanol (0.91 mL, 9.5 mmol) in dichloromethane(20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyldiazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rtovernight. The reaction mixture is diluted with heptane, and filtered.The filtrate is evaporated, and the residue vacuum distilled at 150° C.to give 1.04 g of the product 444. ¹H NMR (CDCl₃) δ 4.21 (q, 2 H), 4.04(s, 2 H), 1.85-1.45 (m, 8 H), 1.29 (t, 3 H)

Step 2

2-[(Cyclopentyloxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (445)

To a solution of the diamine 16 (226 mg, 1.0 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (1.3 mL, 2.6 mmol) followed by asolution of 444 (172 mg, 1.0 mmol) in toluene (1 mL). The solution isheated at 110° C. overnight, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL), EtOAc is added,and the mixture is filtered, and the filtrate dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:MeOH:NH₄OH(95:5:1) followed by treatment with hydrogen chloride in Et₂O gives 60mg of the product 445. ¹H NMR (CDCl₃) δ 7.50-7.25 (m, 2 H), 7.10-6.80(m, 8 H), 4.95-4.70 (m, 1 H), 4.50-4.30 (m, 2 H), 4.20-4.05 (m, 1 H),2.00-1.40 (m, 11 H); MS: m/z 335 (M⁺+1).

Example 1752-[(1-Ethynyl-1-butoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (447)

Step 1

(1-Ethynylbutoxy)acetic acid ethyl ester (446)

To a solution of 1-hexyn-3-ol (981 mg, 10.0 mmol) in dichloromethane (20mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyldiazoacetate (1.0 mL, 9.0 mmol). The reaction mixture is stirred at rtfor 6 h. The reaction mixture is diluted with heptane, and filtered. Thefiltrate is evaporated, and the residue purified by chromatography onsilica gel: elution with EtOAc:heptane (25:75) gives 900 mg of theproduct 446. ¹H NMR (CDCl₃) δ 4.35-4.10 (m, 5 H), 2.43 (s, 1 H),1.90-1.65 (m, 2 H), 1.65-1.40 (m, 2 H), 1.40-1.20 (m, 3 H), 0.95 (t, 3H)

Step 2

2-[(1-Ethynyl-1-butoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (447)

To a solution of the diamine 16 (226 mg, 1.0 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (1.25 mL, 2.5 mmol) followed bya solution of 446 (184 mg, 1.0 mmol) in toluene (1 mL). The solution isheated at 110° C. for 3 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL), EtOAc is added,and the mixture is filtered, and the filtrate dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:MeOH:NH₄OH(95:5:1) followed by treatment with hydrogen chloride in Et₂O gives 131mg of the product 447. ¹H NMR (CDCl₃) δ 7.10-6.80 (m, 10 H), 4.82 (bs, 1H), 4.70 (t, 1 H), 4.43 (t, 1 H), 4.23 (t, 1 H), 2.50 (s, 1 H),1.95-1.65 (m, 5 H), 1.65-1.40 (m, 2 H), 1.10-0.95 (m, 3 H); MS: m/z 346(M⁺+1).

Example 1762-[(Dicyclopropylmethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (449)

Step 1

(Dicyclopropylmethoxy)acetic acid ethyl ester (448)

To a solution of dicyclopropylmethan-1-ol (1.5 mL, 12.7 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (1.26 mL, 12.0 mmol). The reactionmixture is stirred at rt for 48 h. The reaction mixture is diluted withheptane, and filtered. The filtrate is evaporated, and the residue isvacuum distilled at 170° C. to give 1.24 g of the product 448.

Step 2

2-[(Dicyclopropylmethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (449)

To a solution of the diamine 16 (452 mg, 2.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (2.5 mL, 5.0 mmol) followed by asolution of 448 (396 mg, 2.0 mmol) in toluene (1 mL). The solution isheated at 110° C. overnight, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL), EtOAc is added,and the mixture is filtered, and the filtrate is washed with brine,dried (MgSO₄), and filtered. The filtrate is evaporated, and the residueis purified by chromatography on silica gel; elution withdichloromethane:MeOH:NH₄OH (95:5:1) followed by treatment with hydrogenchloride in Et₂O gives 118 mg of the product 449. LC/MS: 2.90 min, m/z361 (M⁺+1).

Example 1772-[(Cyclopentylmethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (451)

Step 1

(Cyclopentylmethoxy)acetic acid ethyl ester (450)

To a solution of cyclopentanemethan-1-ol (1.2 mL, 11.1 mmol) indichloromethane (30 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (1.23 mL, 11.6 mmol). The reactionmixture is stirred at rt overnight. The reaction mixture is diluted withheptane, and filtered. The filtrate is evaporated, and the residue isvacuum distilled at 150° C. to give 1.42 g of the product 450. ¹H NMR(CDCl₃) δ 4.22 (q, 2 H), 4.07 (s, 2 H), 3.40 (d, 2 H), 2.30-2.10 (m, 1H), 11.90-1.65 (m, 2 H), 1.65-1.45 (m, 4 H), 1.40-1.15 (m, 5 H).

Step 2

2-[(Cyclopentylmethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (451)

To a solution of the diamine 16 (452 mg, 2.0 mmol) in toluene (6 mL) isadded 2.0M trimethylaluminum in toluene (2.6 mL, 5.2 mmol) followed by asolution of 450 (372 mg, 2.0 mmol) in toluene (1 mL). The solution isheated at 110° C. for 6 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL),EtOAc:MeOH:dichloromethane (8:1:1) is added, and the mixture isfiltered, and the filtrate is washed with brine, dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:MeOH:NH₄OH(95:5:1) followed by treatment with hydrogen chloride in Et₂O gives 153mg of the product 451. ¹H NMR (CDCl₃) δ 7.20-6.80 (m, 10 H), 5.19 (s, 1H), 5.05 (s, 2 H), 3.56 (d, 2 H), 1.75-1.45 (m, 10 H), 1.35-1.20 (m, 3H); LC/MS: 3.34 min, m/z 349 (M⁺+1).

Example 1782-[(1-Cyclopentyl-1-ethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (453)

Step 1

(1-Cyclopentylethoxy)acetic acid ethyl ester (452)

To a solution of 1-cyclopentylethan-1-ol (1.14 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.03 mmol). The reactionmixture is stirred at rt for 0.5 h. The reaction mixture is diluted withheptane, and filtered. The filtrate is evaporated, and the residue ispurified by chromatography on silica gel; elution with EtOAc:heptane(1:9) gives 0.81 g of the product 452. ¹H NMR (CDCl₃) δ 4.30-4.15 (m, 2H), 4.09 (d, 2 H), 3.25-3.15 (m, 1 H), 2.00-1.78 (m, 2 H), 1.75-1.35 (m,6 H), 1.29 (t, 3 H), 1.15 (d, 3 H).

Step 2

2-[(1-Cyclopentyl-1-ethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (453)

To a solution of the diamine 16 (226 mg, 1.0 mmol) in toluene (3 μL) isadded 2.0M trimethylaluminum in toluene (1.30 mL, 2.6 mmol) followed bya solution of 452 (200 mg, 1.0 mmol) in toluene (0.5 mL). The solutionis heated at 100° C. for 4 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 mL),EtOAc:MeOH:dichloromethane (10:1:2) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:MeOH: (94:6)followed by treatment with hydrogen chloride in Et₂O gives 180 mg of theproduct 453. ¹H NMR (CDCl₃) δ 7.20-6.85 (m, 10 H), 5.30-5.05 (m, 3 H),3.55-3.45 (m, 1 H), 2.05-1.95 (m, 4 H), 1.80-1.55 (m, 6 H), 1.35-0.90(m, 6 H); LC/MS: 3.44 min, m/z 363 (M⁺+1).

Example 1792-[(1,3-Dioxan-5-yl)oxymethyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (455)

Step 1

(1,3-Dioxan-5-yl)acetic acid ethyl ester (454)

To a solution of 1,3-dioxan-5-ol (1.04 g, 10.0 mmol) in dichloromethane(20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyldiazoacetate (0.95 mL, 9.03 mmol). The reaction mixture is stirred at rtfor 4 h. The reaction mixture is diluted with heptane and filtered. Thefiltrate is evaporated, and the residue is purified by chromatography onsilica gel; elution with EtOAc:heptane (1:4) gives 0.65 g of the product454. ¹H NMR (CDCl₃) δ 5.04 (s, 1 H), 4.89 (s, 1 H), 4.25-4.20 (m, 5 H),3.98 (dd, 1 H), 3.78 (dd, 1 H), 3.65 (d, 1 H), 1.29 (t, 3 H).

Step 2

2-[(1,3-Dioxan-5-yl)oxymethyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (455)

To a solution of the diamine 16 (226 mg, 1.0 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (1.30 mL, 2.6 mmol) followed bya solution of 454 (190 mg, 1.0 mmol) in toluene (0.5 mL). The solutionis heated at 100° C. for 6 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (1 μL),EtOAc:MeOH:dichloromethane (10:1:1) is added, and the mixture isfiltered, and the filtrate is washed with brine, dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue is purified bychromatography on silica gel; elution with dichloromethane:MeOH:NH₄OH(95:5:1) followed by treatment with hydrogen chloride in Et₂O gives 162mg of the product 455. ¹H NMR (CDCl₃) δ 7.05-6.85 (m, 10 H), 5.30-5.05(m, 3 H), 4.90 (d, 1 H), 4.75 (d, 1 H), 4.32 (s, 1 H), 3.95-3.50 (m, 5H), 2.00-1.90 (m, 3 H); LC/MS: 2.35 min, m/z 353 (M⁺+1).

Example 1802-(Methoxymethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (456)

To a solution of the diamine 16 (170 mg, 0.75 mmol) in toluene (2.5 mL)is added 2.0M trimethylaluminum in toluene (0.980 mL, 1.96 mmol)followed by methoxyacetic acid methyl ester (0.74 mL, 0.75 mmol), andthe solution is heated at 90° C. for 2.5 h, then cooled to rt. Thereaction mixture is quenched with sat. sodium bicarbonate solution (1.5mL) and EtOAc is added, and the mixture is filtered, and the filtratedried (MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on reversed phase silica gel; gradientelution with acetonitrile/0.1% TFA:water/0.1% TFA (20:80-100:0) gives 51mg of the product 456. ¹H NMR (DMSO-d₆) δ 8.0 (d, 1 H), 7.4-7.0 (m, 10H), 5.48 (d, 1 H), 3.78 (s, 2 H), 3.15 (s, 3 H), 1.62 (s, 3 H); LC/MS:2.63 min, m/z 282 (M⁺+1).

Example 1812-(Isopropoxymethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (457)

To a solution of the diamine 16 (170 mg, 0.75 mmol) in toluene (2.5 mL)is added 2.0M trimethylaluminum in toluene (0.980 mL, 1.96 mmol)followed by isopropoxyacetic acid ethyl ester (405) (110 mg, 0.75 mmol),and the solution is heated at 90° C. for 2.5 h, then cooled to rt. Thereaction mixture is quenched with sat. sodium bicarbonate solution (1.5mL) and EtOAc is added, and the mixture is filtered, and the filtratedried (MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on reversed phase silica gel; gradientelution with acetonitrile/0.1% TFA:water/0.1% TFA (20:80-100:0) gives 44mg of the product 457. ¹H NMR (DMSO-d₆) δ 7.1-6.8 (m, 10 H), 4.73 (bs, 1H), 4.21 (s, 2 H), 3.80 (m, 1 H), 3.32 (s, 3 H), 1.2-1.9 (m, 6 H);LC/MS: 3.12 min, m/z 309 (M⁺+1).

Example 1822-[[(Tetrahydropyran-2-yl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (459)

Step 1

(Tetrahydropyran-2-yl)methoxyacetic acid ethyl ester (458).

To a solution of tetrahydropyran-2-methanol (1.13 mL, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg)followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reactionmixture is stirred at rt for 20 min. To the reaction mixture is addedMeOH (0.5 mL), and the solvents rotary evaporated. The residue ispurified by chromatography on silica gel; elution with EtOAc:heptane(30:70) gives 1.66 g of the product 458. ¹H NMR (CDCl₃) δ 4.3-4.1 (m, 4H), 4.0 (m, 1 H), 3.6-3.4 (m, 4 H), 1.85 (m, 1 H), 1.6-1.3 (m, 5 H),1.25 (t, 3 H); MS: m/z 203 (M⁺+1).

Step 2

2-[[(Tetrahydropyran-2-yl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (459)

To a solution of the diamine 16 (136 mg, 0.60 mmol) in toluene (2.5 mL)is added 2.0M trimethylaluminum in toluene (0.78 mL, 1.56 mmol) followedby 458 (121 mg, 0.6 mmol), and the solution is heated at 90° C. for 4 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (1 mL) and EtOAc is added, and the mixture isfiltered, and the filtrate dried (MgSO₄), and filtered. The filtrate isevaporated, and the residue purified by chromatography on reversed phasesilica gel; gradient elution with acetonitrile/0.1% TFA:water/0.1% TFA(40:60-100:0) gives 89 mg of the product 459. ¹H NMR (DMSO-d₆) δ 10.75(s, 1 H), 7.1-6.9 (m, 10 H), 5.35 (s, 1 H), 4.8 (s, 2 H), 3.9-3.5 (m, 4H), 3.4 (m, 1 H), 1.94 (s, 3 H), 1.80 (m, 1 H), 1.6-1.4 (m, 4 H), 1.30(m, 1 H); LC/MS: 2.64 min, m/z 365 (M⁺+1).

Example 1832-[[(Cyclopropyl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (463)

Step 1

(Cyclopropyl)methoxyacetic acid ethyl ester (462)

To a solution of cyclopropylmethanol (720 mg, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at rt for 5 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 150° C. to give 1.22 g of the product462. ¹H NMR (CDCl₃) δ 4.2 (q, 2H), 4.09 (s, 2H), 3.37 (d, 2H), 1.27 (t,3H), 1.09 (m, 1H), 0.56-0.51 (m, 2H), 0.25-0.2 (m, 211); MS: m/z 191(M⁺)

Step 2

2-[[(Cyclopropyl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (463)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followed by462 (79 mg, 0.50 mmol), and the solution is heated at 80° C. for 3 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel; elutionwith acetonitrile:water/0.1% TFA gives 102 mg of the product 463. ¹H NMR(DMSO-d₆) δ 11.0 (s, 1H), 10.79 (s, 1H), 7.1-6.9 (m, 10H), 5.35 (s, 1H),4.77 (s, 2H), 3.52 (d, 2H), 1.94 (s, 3H), 1.15 (m, 1H), 0.58 (m, 2H),0.31 (m, 2H); LC/MS: 2.62 min, nm/z 321 (M⁺+1).

Example 1842-[(2-Chlorophenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (466)

Step 1

(2-Chlorophenoxy)acetic acid ethyl ester (465)

To a solution of 2-chlorophenol (2.06 mL, 19.9 mmol) in DMF (40 mL) isadded potassium carbonate (3.03 g, 21.9 mmol) and ethyl bromoacetate(2.3 mL, 20.7 mmol), and the mixture is stirred at 80° C. for 18 h. Et₂Ois added, and the mixture is washed with water, brine, dried (MgSO₄),and filtered. The filtrate is evaporated, and the residue is purified bychromatography in silica gel; elution with EtOAc:dichloromethane:hexane(10:5:85) gives 4.17 g of the product 465. ¹H NMR (CDCl₃) δ 7.38 (d,1H), 7.21 (t, 1H), 6.92 (t, 1H), 6.84 (d, 1H), 4.70 (s, 2H), 4.27 (q,2H), 1.29 (t, 3H); MS: m/z 215, 217 (M⁺+1).

Step 2

2-[(2-Chlorophenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolehydrochloride (466)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (1.5 mL)is added 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followedby 465 (103 mg, 0.50 mmol), and the solution is heated at 80° C. for 2.5h, then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on silica gel; elution withdichloromethane:MeOH (95:5) followed by treatment with hydrogen chloridein Et₂O gives 141 mg of the product 466. ¹H NMR (DMSO-d₆) δ 11.4 (bs,1H), 11.2 (bs, 1H), 7.57 (dd, 1H), 7.5-7.35 (m, 2H), 7.2-6.95 (m, 11H),5.53 (s, 2H), 5.41 (s, 1H), 1.96 (s, 3H); LC/MS: 2.77 min, m/z 377, 379(M⁺+1).

Example 1852-(1-Phenoxyethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (468)

Step 1

N-(2-Amino-1,2-diphenylethyl)-2-phenoxypropionamide (467)

To a solution of 2-phenoxypropanoic acid (84 mg, 0.5 mmol) indichloromethane (2 mL) is added DMF (0.010 mL) followed by oxalylchloride (0.126 mL, 1.44 mmol), and the solution is stirred at rt for 30min., then concentrated under nitrogen. The residue is dissolved indichloromethane (1 mL), and is added to a solution of the diamine 16(113 mg, 0.5 mmol) in dichloromethane (1.5 mL), and the reaction mixtureis stirred at rt for 2 h. The reaction mixture is made basic with sat.sodium bicarbonate solution, and the organic layer is separated andevaporated. The residue is purified by chromatography on silica gel;elution with dichloromethane:MeOH (95:5) gives 166 mg of the product467. ¹H NMR (CDCl₃ Diastereomer A) δ 7.78 (bd, 1H), 7.4-6.8 (m, 13H),6.40 (d, 2H), 5.16 (d, 1H), 4.76 (q, 1H), 1.57 (s, 3H), 1.53 (d, 3H); ¹HNMR (CDCl₃ Diastereomer B) δ 7.63 (bd, 1H), 7.4-6.8 (m, 13H), 6.78 (d,2H), 5.13 (d, 1H), 4.69 (q, 1H), 1.67 (d, 3H), 1.22 (s, 3H); LC/MS: 3.00min, m/z 375 (M⁺+1).

Step 2

2-(1-Phenoxyethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (468)

To a solution of 467 (160 mg, 0.44 mmol) in toluene (2.5 mL) is added2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol), and the solutionheated at 93° C. for 2.5 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.4 mL) andEtOAc:dichloromethane:MeOH (2:2:1) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue purified bychromatography on reversed phase silica gel; elution withacetonitrile:water/0.1% TFA gives 105 mg of the product 468. ¹H NMR(DMSO-d₆) δ 11.25 (bd, 1H), 11.07 (bs, 1H), 7.45-7.38 (m, 2H), 7.2-6.9(m, 10H), 6.9-6.74 (m, 3H), 5.73 (q, 1H), 5.34 (d, 1H), 1.90 (s, 3H),1.79 (d, 3H); LC/MS: 3.13 min, m/z 357 (M⁺+1).

Example 1862-[(Cyclobutoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (470)

Step 1

Cyclobutoxyacetic acid ethyl ester (469)

To a solution of cyclobutanol (720 mg, 10.0 mmol) in dichloromethane (20mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyldiazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rtfor 30 min. The reaction mixture is diluted with heptane, filteredthrough Celite, and the filtrate is evaporated and the residue is vacuumdistilled at 140° C. to give 1.00 g of the product 469. ¹H NMR (CDCl₃) δ4.21 (q, 2H), 4.03 (m, 1H), 3.98 (s, 2H), 2.28-2.15 (m, 2H), 2.08-1.95(m, 2H), 1.7 (q, 1H), 1.50 (m, 1H), 1.28 (t, 3H)

Step 2

2-[(Cyclobutoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (470)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (1.5 mL)is added 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followedby 469 (79 mg, 0.50 mmol), and the solution is heated at 90° C. for 11h, then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel; elutionwith acetonitrile:water/0.1% TFA gives 89 mg of the product 470. ¹H NMR(DMSO-d₆) δ 11.01 (bs, 1H), 10.79 (bs, 1H), 7.1-6.9 (m, 10H), 5.34 (s,1H), 4.64 (s, 2H), 4.20 (m, 1H), 2.3-2.2 (m, 2H), 2.09-1.95 (m, 2H),1.93 (s, 3H), 1.72 (m, 1H), 1.51 (m, 1H); LC/MS: 3.05 min, m/z 321(M⁺+1).

Example 1872-[(1-Cyclopropyl-1-ethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (472)

Step 1

(1-Cyclopropyl-1-ethoxy)acetic acid ethyl ester (471)

To a solution of cyclopropyl-1-ethanol (860 mg, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at rt for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 130° C. to give 1.11 g of the product471. ¹H NMR (CDCl₃) δ 4.12 (s, 2H), 4.10 (q, 2H), 2.86 (m, 1H),1.25-1.15 (m, 6H), 0.8-0.7 (m, 1H), 0.55-0.3 (m, 3H), 0.05-0.02 (m, 1H);MS: m/z 173 (M⁺+1).

Step 2

2-[(1-Cyclopropyl-1-ethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (472)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (1.5 mL)is added 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followedby 471 (86 mg, 0.50 mmol), and the solution is heated at 90° C. for 11h, then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel; elutionwith acetonitrile:water/0.1% TFA gives 76 mg of the product 472. ¹H NMR(DMSO-d₆) δ 10.93 (s, 1H), 10.72 (s, 1H), 7.1-6.9 (m, 10H), 5.35 (s,1H), 4.82 (s, 2H), 3.08 (m, 1H), 1.30 and 1.29 (two d, 3H combined),0.93 (m, 1H), 0.62 (m, 1H), 0.50 (m, 2H), 0.18 (m, 1H); LC/MS: 3.10 min,m/z 335 (M⁺+1).

Example 1882-[(2-Methoxy-1-methylethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (474)

Step 1

(2-Methoxy-1-methylethoxy)acetic acid ethyl ester (473)

To a solution of 1-methoxy-2-propanol (900 mg, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at rt for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 133° C. to give 1.03 g of the product473. ¹H NMR (CDCl₃) δ 4.20 (q, 2H), 3.72 (m, 1H), 3.45 (dd, 1H), 3.37(dd, 1H), 3.35 (s, 3H), 1.27 (t, 3H), 1.19 (d, 3H).

Step 2

2-[(2-Methoxy-1-methylethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (474)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (1.5 mL)is added 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followedby 473 (88 mg, 0.50 mmol), and the solution is heated at 90° C. for 11h, then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel; elutionwith acetonitrile:water/0.1% TFA gives 56 mg of the product 474. ¹H NMR(DMSO-d₆) δ 7.05-6.85 (m, 10H), 4.80 (s, 1H), 4.35 (s, 1H), 3.83 (m,1H), 3.42 (m, 1H), 3.35 (m, 1H), 3.28 (s, 3H), 1.66 (s, 3H), 1.17 and1.18 (two d, 3H combined); LC/MS: 2.95 min, m/z 339 (M⁺+1).

Example 1892-[(1-Benzopyran-4-yloxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolinehydrochloride (476)

Step 1

[(1-Benzopyran-4-yloxy)methyl]acetic acid ethyl ester (475)

To a solution of 4-chromanol (1.5 g, 10.0 mmol) in dichloromethane (20mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyldiazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rtfor 30 min. The reaction mixture is diluted with heptane, filteredthrough Celite, and the filtrate is evaporated and the residue purifiedby chromatography on silica gel; elution withEtOAc:dichloromethane:hexane (10:20:70) gives 1.81 g of the product 475.¹H NMR (CDCl₃) δ 7.35 (dd, 1H), 7.22 (dt, 1H), 6.90 (t, 1H), 6.84 (d,1H), 4.56 (m, 1H), 4.36 (dd, 1H), 4.29 (dd, 1H), 4.23 (q, 2H), 4.19 (s,2H), 2.18 (m, 1H), 2.05 (m, 1H), 1.30 (t, 3H); MS: m/z 236 (M⁺+1).

Step 2

2-[(1-Benzopyran-4-yloxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazolinehydrochloride (476)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followed by475 (118 mg, 0.50 mmol), and the solution is heated at 80° C. for 3 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on silica gel; elution withdichloromethane:MeOH (95:5) followed by treatment with hydrogen chloridein Et₂O gives 65 mg of the product 476. ¹H NMR (DMSO-d₆) δ 11.0 (d, 1H),10.77 (s, 1H), 7.45 (m, 2H), 7.29 (m, 2H), 7.06-6.9 (m, 9H), 6.85 (dd,1H), 5.30 (s, 1H), 5.00 (d, 1H), 4.87 (d, 1H), 4.75 (m, 1H), 4.3 (m,2H), 2.3-2.2 (m, 1H), 2.15-2.0 (m, 1H), 1.91 and 1.90 (two s, 3Hcombined); LC/MS: 2.80 min, m/z 399 (M⁺+1).

Example 1902-[[(Tetrahydrofuran-2-yl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole(478)

Step 1

(Tetrahydrofuran-2-ylmethoxy)acetic ethyl ester (477)

To a solution of tetrahydrofurfuryl alcohol (1.02 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixtureis stirred at rt for 30 min. The reaction mixture is diluted withheptane, filtered through Celite, and the filtrate is evaporated and theresidue is vacuum distilled at 130° C. to give 1.02 g of the product477. ¹H NMR (CDCl₃) δ 4.11 (q, 2H), 4.10 (s, 2H), 3.93 (m, 1H), 3.72 (m,1H), 3.61 (m, 1H), 3.44 (m, 2H), 1.95-1.75 (m, 3H), 1.61-1.53 (m, 1H),1.20 (t, 3H).

Step 2

2-[[(Tetrahydrofuran-2-yl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole(478)

To a solution of the diamine 16 (113 mg, 0.50 mmol) in toluene (2 mL) isadded 2.0M trimethylaluminum in toluene (0.65 mL, 1.30 mmol) followed by477 (94 mg, 0.50 mmol), and the solution is heated at 80° C. for 3 h,then cooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.4 mL) and EtOAc:dichloromethane:MeOH (2:2:1) isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on silica gel; elution withdichloromethane:MeOH (95:5) gives 126 mg of the product 478. ¹H NMR(DMSO-d₆) δ 7.06-6.94 (m, 10H), 5.16 (s, 1H), 4.66 (s, 2H), 4.07 (m,1H), 3.78 (m, 1H), 3.66 (m, 2H), 3.60 (m, 1H), 1.993 (m, 1H), 1.85 (m,3H), 1.61 (m, 1H); LC/MS: 2.51 min, m/z 351 (M⁺+1).

Example 1912-[(Phenoxy)methyl]-cis-4,5-diphenyl-4,5-dimethyl-4,5-dihydro-1H-imidazoletrifluoroacetate (481)

Step 1

cis-3,4-Diphenyl-3,4-dimethyl-1,2,5-thiadiazolidine-1,1-dioxide (479)

To a suspension of 3,4-diphenyl-1,1-dioxo-1,2,5-thiadiazole (14) (2.7 g,10.0 mmol), in toluene (40 mL) is added THF (10 mL) followed by 3.0Mmethylmagnesium bromide in Et₂O (14 mL, 42 mmol). The homogenoussolution is stirred at rt for 4 h, quenched with ammonium chloridesolution, washed with brine, dried (MgSO₄), and filtered. The filtrateis evaporated and the residue purified by chromatography on silica gel;elution with dichloromethane:EtOAc:hexane (10:20:70) gives 2.61 g of theproduct 479. MS: m/z 303 (M⁺+1).

Step 2

cis-2,3-Diphenylbutane-2,3-diamine (480)

A suspension of 479 (2.61 g, 8.63 mmol) in 2M HBr (75 mL) containingphenol (3.12 g) is stirred and heated at reflux for 18 h. The mixture iscooled to rt, extracted with EtOAc, and the aqueous solution is cooled(ice bath) and made basic (pH 14) with sodium hydroxide. The basicsolution is extracted with Et₂O, and the extract is washed with water,brine, then dried (Na₂SO₄), and filtered. The filtrate is evaporated,and the residue purified by chromatography on silica gel; elution withdichloromethane:Et₂O:MeOH (75:20:5) gives 206 mg of the product 480. ¹HNMR (DMSO-d₆) δ 7.16 (m, 10H), 1.8 (bs, 4H), 1.37 (s, 6H); MS: m/z 241(M⁺+1).

Step 3

2-[(Phenoxy)methyl]-cis-4,5-diphenyl-4,5-dimethyl-4,5-dihydro-1H-imidazoletrifluoroacetate (481)

To a solution of the diamine 480 (84 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol) followedby phenoxyacetic acid ethyl ester (430) (94 mg, 0.36 mmol), and thesolution is heated at 85° C. for 3 h, then cooled to rt. The reactionmixture is quenched with sat. sodium bicarbonate solution (0.4 mL) andEtOAc:MeOH (2:1) is added, and the mixture is filtered. The filtrate isevaporated, and the residue purified twice by chromatography on reversedphase silica gel; gradient elution with acetonitrile:water/0.1% TFA(40:60-100:0) gives 7 mg of the product 481. ¹H NMR (DMSO-d₆) δ 7.4-7.3(m, 2H), 7.2-6.9 (m, 9H), 6.9-6.8 (m, 4H), 5.7 (bs, 2H), 1.97 (bs, 6H);LC/MS: 3.20 min, m/z 357 (M⁺+1).

Example 1922-[[(Cyclopentyl)methoxy]methyl]-cis-(5-methoxyphenyl-4-phenyl)-4,5-dihydro-1H-imidazolehydrochloride (486)

Step 1

(S)-[(N-Methoxy-N-methylcarbamoyl)phenylmethyl]carbamic acid benzylester (482)

To a solution of Z-L-phenylglycine (5.0 g, 17.5 mmol) in dichloromethane(35 mL) is added 1,1′-carbonyldimidazole (3.13 g, 19.3 mmol), and thesolution is stirred at rt for 0.5 h. To the solution is addedN,O-dimethylhydroxylamine hydrochloride (1.88 g, 19.3 mmol), and themixture is stirred at rt overnight. To the reaction mixture is addedammonium chloride solution and EtOAc, and the organic layer isseparated, washed with brine, dried (MgSO₄), and filtered. The filtrateis evaporated to give 5.65 g of the product 482. ¹H NMR (CDCl₃) δ7.50-7.20 (m, 10 H), 6.10 (d, 1 H), 5.78 (d, 1 H), 5.20-5.00 (m, 2 H),3.43 (s, 3 H), 3.18 (s, 3 H); MS: m/z 329 (M⁺+1).

Step 2

(S)-[(4-Methoxyphenyl)-2-oxo-1-phenylethyl]carbamic acid benzyl ester(483)

To a cold (0° C.) solution of the amide 482 (328 mg, 1.0 mmol) in THF(20 mL) is added 0.5M 4-methoxyphenylmagnesium bromide in THF (8.0 mL,4.0 mmol), and the mixture is allowed to come to rt and stirred at thistemperature for 3 h. The reaction mixture is poured into a mixture ofammonium chloride/ice followed by the addition of EtOAc. The organiclayer is separated, washed with brine, dried (MgSO₄), and filtered. Thefiltrate is evaporated, and the residue purified by chromatography onsilica gel; elution with heptane:EtOAc (85:15) gives 2.12 g of theproduct 483. ¹H NMR (CDCl₃) δ 7.95 (d, 2 H), 7.45-7.20 (m, 10 H), 6.88(d, 2 H), 6.50-6.20 (m, 2 H), 5.25-5.00 (m, 2 H), 3.81 (s, 3 H)

Step 3

(S)-[2-(Hydroxylimino)-2-(4-methoxyphenyl)-1-phenylethyl]carbamic acidbenzyl ester (484)

To a solution of the ketone 483 (2.47 g, 6.6 mmol) in EtOH (35 mL) isadded hydroxylamine hydrochloride (1.83 g, 26.4 mmol) followed bypyridine (2.13 mL, 26.4 mmol). The mixture is stirred at 80° C. for 8 h.The reaction mixture is cooled, the solvent is evaporated, and theresidue dissolved in EtOAc, washed with water, brine, then dried(MgSO₄), and filtered. The filtrate is evaporated, and the residuepurified by chromatography on silica gel; elution with heptane:EtOAc(7:3) gives 1.95 g of the product 484. ¹H NMR (CDCl₃) δ 7.55 (d, 2 H),7.50-7.10 (m, 10 H), 7.00-6.70 (m, 2 H), 6.50-6.35 (m, 1 H), 5.30-5.00(m, 2 H), 3.80 (d, 3 H); MS: m/z 391 (M⁺+1).

Step 4

cis-[2-(4-Methoxyphenyl)-1-phenyl]ethane-1,2-diamine (485)

To a solution of the oxime 484 (2.13 g, 5.45 mmol) in EtOH (50 mL) undernitrogen is added 10% palladium-on-carbon (1 g), and the mixture treatedwith hydrogen (50 psi), and shaken at rt for 4 h. The reaction mixtureis filtered, the filtrate evaporated, and the residue triturated withEt₂O to give 1.0 g of the product 485. ¹H NMR (CDCl₃) δ 7.50-7.25 (m, 7H), 6.90 (d, 2 H), 4.00 (s, 2 H), 3.80 (s, 3 H), 1.61 (bs, 4 H); MS: m/z242 (M⁺+1).

Step 5

2-[[(Cyclopentyl)methoxy]methyl]-cis-(5-methoxyphenyl-4-phenyl)-4,5-dihydro-1H-imidazolehydrochloride (486)

To a solution of the diamine 485 (242 mg, 1.0 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (1.25 mL, 2.5 mmol) followed bya solution of 2-(cyclopentylmethoxy)acetic acid ethyl ester (450) (186mg, 1.0 mmol) in toluene (1 mL). The solution is heated at 110° C. for 2h, and stirred at rt overnight. The reaction mixture is quenched withsat. sodium bicarbonate solution (0.4 mL), EtOAc is added, and themixture is filtered. The filtrate is evaporated, and the residue ispurified by chromatography on silica gel; elution withdichloromethane:MeOH:NH₄OH (95:5:1) followed by treatment with hydrogenchloride in Et₂O gives 115 mg of the product 486. ¹H NMR (CDCl₃) δ7.15-7.7.00 (m, 3 H), 7.00-6.90 (m, 2 H), 6.90-6.75 (m, 1 H), 6.65-6.50(m, 2 H), 5.30 (s, 1 H), 5.25 (s, 2 H), 4.40 (s, 2 H), 3.70 (s, 3 H),3.50 (d, 2 H), 2.30-2.10 (m, 1 H), 1.90-1.15 (m, 8 H); MS: m/z 365(M⁺+1).

Example 1932-(3-Ethoxy-1-ethyl-1-propoxymethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoleditrifluoroacetate (488)

Step 1

(3-Ethoxy-1-ethylpropoxy)acetic acid ethyl ester (487)

To a solution of 1-ethoxy-3-pentanol (1.32 g, 10.0 mmol) indichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg)followed by ethyl diazoacetate (1.0 mL, 9.5 mmol). The reaction mixtureis stirred at rt for 2 h. The reaction mixture is diluted with heptane,filtered through Celite, and the filtrate is evaporated. The residue ispurified by chromatography on silica gel; elution with EtOAc:heptane(1:3) gives 660 mg the product 487.

Step 2

2-(3-Ethoxy-1-ethyl-1-propoxymethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazoleditrifluoroacetate (488)

To a solution of the diamine 16 (226 mg, 1.0 mmol) in toluene (3 mL) isadded 2.0M trimethylaluminum in toluene (1.25 mL, 2.50 mmol) followed bya solution of 487 (218 mg, 1.0 mmol) in toluene (1 mL), and the solutionis heated at 110° C. for 4 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.4 mL), and EtOAc isadded, and the mixture is washed with brine, dried (MgSO₄), andfiltered. The filtrate is evaporated, and the residue purified bychromatography on silica gel; elution with dichloromethane:MeOH:NH₄OH(95:5:1)) gives 91 mg the product 488. ¹H NMR (CDCl₃) δ 7.10-6.80 (m, 10H), 4.90-4.75 (m, 1 H), 4.60-4.30 (m, 2 H), 3.80-3.30 (m, 5 H),1.95-1.75 (m, 5 H), 1.75-1.55 (m, 2 H), 1.20-1.10 (m, 3 H), 1.10-0.90(m, 3 H); LC/MS: 2.94 min, m/z 381 (M⁺+1).

Example 1942-(Phenoxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (490)

To a solution of 2-methyl-1-phenylpropane-1-2-diamine (164 mg, 1.0 mmol,J. Org. Chem., 1995, 60, 7411) in toluene (3 mL) is added 2.0Mtrimethylaluminum in toluene (1.3 mL, 2.6 mmol). The resulting solutionis stirred for 15 min, then a solution of phenoxyacetic acid ethyl ester(430) (180 mg, 1.0 mmol) in toluene (1 mL) is added. The solution isheated at 90° C. for 2 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (2 mL) and EtOAc isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA to give 65 mg of theproduct 490. ¹H NMR (CDCl₃) δ 11.50 (bs, 1 H), 9.73 (bs, 1 H), 7.4-7.3(m, 5 H), 7.2-7.0 (m, 5 H), 5.3-5.2 (m, 2 H), 4.93 (s, 1 H), 1.61 (s, 3H), 0.91 (s, 3 H); LC/MS: 3.09 min, m/z 281 (M⁺+1).

Example 1952-(Benzyloxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (491)

To a solution of 2-methyl-1-phenylpropane-1-2-diamine (164 mg, 1.0 mmol,J. Org. Chem., 1995, 60, 7411) in toluene (3 mL) is added 2.0Mtrimethylaluminum in toluene (1.3 mL, 2.6 mmol). The resulting solutionis stirred for 15 min, then a solution of benzyloxyacetic acid ethylester (390) (194 mg, 1.0 mmol) in toluene (1 mL) is added. The solutionis heated at 90° C. for 2 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (2 mL) and EtOAc isadded, and the mixture is filtered. The filtrate is evaporated, and theresidue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA to give 77 mg of theproduct 491. ¹H NMR (CDCl₃) δ 11.08 (bs, 1 H), 9.17 (bs, 1 H), 7.4-7.3(m, 8 H), 7.2-7.1 (m, 2 H), 4.87 (s, 1 H), 4.75 (s, 2 H), 4.64 (s, 2 H),1.58 (s, 3 H), 0.87 (s, 3 H); LC/MS: 3.10 min, m/z 295 (M⁺+1).

Example 1962-(3-fluorobenzyloxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (492)

To a solution of 2-methyl-1-phenylpropane-1-2-diamine (164 mg, 1.0 mmol,J. Org. Chem., 1995, 60, 7411) in toluene (3 mL) is added 2.0Mtrimethylaluminum in toluene (1.3 mL, 2.6 mmol). The resulting solutionis stirred for 15 min, then a solution of 3-fluorobenzyloxyacetic acidethyl ester (392) (212 mg, 1.0 mmol) in toluene (1 mL) is added. Thesolution is heated at 90° C. for 2 h, then cooled to rt. The reactionmixture is quenched with sat. sodium bicarbonate solution (2 mL) andEtOAc is added, and the mixture is filtered. The filtrate is evaporated,and the residue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA to give 98 mg of theproduct 492. ¹H NMR (CDCl₃) δ 10.93 (bs, 1 H), 9.21 (bs, 1 H), 7.4-7.3(m, 4 H), 7.2-7.0 (m, 5 H), 4.92 (s, 1 H), 4.75 (s, 2 H), 4.64 (s, 2 H),1.60 (s, 3 H), 0.89 (s, 3 H); LC/MS: 3.20 min, m/z 313 (M⁺+1).

Example 1972-(3-fluorophenoxymethyl)-4,4-dimethyl-5-phenyl-4,5-dihydro-1H-imidazoletrifluoroacetate (493)

To a solution of 2-methyl-1-phenylpropane-1-2-diamine (164 mg, 1.0 mmol,J. Org. Chem., 1995, 60, 7411) in toluene (3 mL) is added 2.0Mtrimethylaluminum in toluene (1.3 mL, 2.6 mmol). The resulting solutionis stirred for 15 min, then a solution of 3-fluorophenoxyacetic acidethyl ester (432) (198 mg, 1.0 mmol) in toluene (1 mL) is added. Thesolution is heated at 90° C. for 2 h, then cooled to rt. The reactionmixture is quenched with sat. sodium bicarbonate solution (2 mL) andEtOAc is added, and the mixture is filtered. The filtrate is evaporated,and the residue purified by chromatography on reversed phase silica gel;gradient elution with acetonitrile:water/0.1% TFA to give 107 mg of theproduct 493. ¹H NMR (CDCl₃) δ 11.41 (bs, 1 H), 10.22 (bs, 1 H), 7.4-7.2(m, 4 H), 7.15-7.12 (m, 2 H), 6.8-6.7 (m, 3 H), 5.17 (s, 2 H), 4.92 (s,1 H), 1.58 (s, 3 H), 0.87 (s, 3 H); LC/MS: 3.13 min, m/z 299 (M⁺+1).

Example 1982-Phenoxymethyl-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (500)

Step 1

3-(Pyridin-3-yl)-4-phenyl-1,2,5-thiadiazole-1,1-dioxide hydrochloride(497)

Hydrogen chloride gas is bubbled into a solution of1-phenyl-2-(pyridin-3-yl)ethan-1,2-dione (1.63 g, 7.7 mmol, J. Org.Chem., 1999, 64, 6102) and sulfamide (750 mg, 7.7 mmol) in methanol (10mL) until the solution begins to reflux. The gas flow is turned off, andthe solution stirred at 65° C. for 3 h then cooled to rt. The solid thatformed is filtered and dried to give 2.06 g of the product 497. MS: m/z272 (M⁺+1).

Step 2

cis-3-(Pyridin-3-yl)-4-phenyl-2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide(498)

To a solution of 3-(pyridin-3-yl)-4-phenyl-1,2,5-thiadiazole-1,1-dioxidehydrochloride (497) (1.86 g, 6.6 mmol) in THF:methanol (20 mL, 1:1) isadded sodium borohydride (1.38 g, 36.0 mmol in batches; 230 mg each). Oncomplete addition, the solution is stirred for 1 h, then quenched with5N HCl. The solution is then brought to pH 6 by the addition of sat.sodium bicarbonate solution, extracted with EtOAc, the organic phase isseparated, washed with brine, dried (MgSO₄), and filtered. The filtrateis concentrated to give 1.64 g of the product 498. ¹H NMR (DMSO-d₆) δ8.28 (bs, 1H), 8.20 (bs, 1H), 8.15 (bs, 1H), 7.70 (m, 2H), 7.44 (d, 1H),7.15-7.0 (5H), 5.19 (d, 1H), 5.17 (d, 1H); MS: m/z 276 (M⁺+1).

Step 3

erythro-1-Phenyl-2-(pyridin-3-yl)ethylene-1,2-diamine (499)

To a solution ofcis-3-(pyridin-3-yl)-4-phenyl-2,3-dihydro-1,2,5-thiadiazole-1,1-dioxide(498) (1.8 g, 6.6 mmol) in 2M HBr (75 mL) is added phenol (3.12 g, 33.2mmol). The mixture is heated to reflux and stirred for 18 h then cooledto rt, and extracted with EtOAc. The aqueous phase is basified to pH 14with solid sodium hydroxide, then concentrated. The solid residue ismixed thoroughly with EtOAc:methanol:dichloromethane (1:1:5). Theinsoluble solid is filtered, and the filtrate concentrated to give 442mg of the product 499. ¹H NMR (DMSO-d₆) δ 8.37 (d, 1H), 8.26 (bs, 1H),7.56 (d, 1H), 7.3-7.1 (m, 6H), 3.97 (bs, 2H), 1.78 (bs, 4H); MS: m/z 214(M⁺+1).

Step 4

2-Phenoxymethyl-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (500)

To a solution of the diamine 499 (73 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol). Theresulting solution is stirred for 10 min, then phenoxyacetic acid ethylester (430) (63 mg, 0.35 mmol) is added. The solution is heated at 80°C. for 2.5 h, then cooled to rt. The reaction mixture is quenched withsat. sodium bicarbonate solution (0.45 mL) andEtOAc:methanol:dichloromethane (1:1:5) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue purified bychromatography on reversed phase silica gel; gradient elution withacetonitrile:water/0.1% TFA to give 79 mg of the product 500. ¹H NMR(DMSO-d₆) δ 11.17 (s, 1H), 11.09 (s, 1H), 8.32 (bs, 2H), 7.5-7.4 (m,3H), 7.16-7.03 (m, 9H), 5.94 (d, 1H), 5.91 (d, 1H), 5.44 (s, 2H); LC/MS:2.42 min, m/z 330 (M⁺+1).

Example 1992-[(3-Fluorophenoxy)methyl]-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (501)

To a solution of the diamine 499 (73 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol). Theresulting solution is stirred for 10 min, then 3-fluorophenoxyaceticacid ethyl ester (432) (74 mg, 0.35 mmol) is added. The solution isheated at 80° C. for 2.5 h, then cooled to rt. The reaction mixture isquenched with sat. sodium bicarbonate solution (0.45 mL) andEtOAc:methanol:dichloromethane (1:1:5) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue purified bychromatography on reversed phase silica gel; gradient elution withacetonitrile:water/0.1% TFA to give 89 mg of the product 501. ¹H NMR(DMSO-d₆) δ 11.17 (s, 1H), 11.09 (s, 1H), 8.32 (bs, 2H), 7.5-7.43 (m,2H), 7.20-6.92 (m, 9H), 5.94 (d, 1H), 5.91 (d, 1H), 5.47 (s, 2H); LC/MS:2.50 min, m/z 348 (M⁺+1).

Example 2002-Cyclohexyloxymethyl-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (502)

To a solution of the diamine 499 (73 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol). Theresulting solution is stirred for 10 min, then cyclohexyloxyacetic acidethyl ester (407) (65 mg, 0.35 mmol) is added. The solution is heated at80° C. for 2.5 h, then cooled to rt. The reaction mixture is quenchedwith sat. sodium bicarbonate solution (0.45 mL) andEtOAc:methanol:dichloromethane (1:1:5) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue purified bychromatography on reversed phase silica gel; gradient elution withacetonitrile:water/0.1% TFA to give 43 mg of the product 502. ¹H NMR(DMSO-d₆) δ 10.81 (s, 1H), 10.73 (s, 1H), 8.39 (bm, 2H), 7.48 (m, 2H),7.18-7.05 (m, 5H), 5.88 (d, 1H), 5.86 (d, 1H), 4.76 (s, 2H), 3.56 (m,1H), 1.93 (m, 2H), 1.73 (m, 2H), 1.53 (m, 1H), 1.42-1.09 (m, 5H); LC/MS:2.57 min, m/z 336 (M⁺+1).

Example 2012-Phenylthiomethyl-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (503)

To a solution of the diamine 499 (73 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol). Theresulting solution is stirred for 10 min, then phenylthioacetic acidethyl ester (74 mg, 0.35 mmol) is added. The solution is heated at 80°C. for 2.5 h, then cooled to rt. The reaction mixture is quenched withsat. sodium bicarbonate solution (0.45 mL) andEtOAc:methanol:dichloromethane (1:1:5) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue purified bychromatography on reversed phase silica gel; gradient elution withacetonitrile:water/0.1% TFA to give 69 mg of the product 503. ¹H NMR(DMSO-d₆) δ 11.01 (s, 1H), 10.93 (s, 1H), 8.24 (bs, 1H), 8.10 (bs, 1H),7.65 (d, 2H), 7.54-7.42 (m, 3H), 7.05-7.03 (m, 5H), 6.72 (m, 2H), 5.84(d, 1H), 5.79 (d, 1H), 4.43 (s, 2H); LC/MS: 2.44 min, m/z 346 (M⁺+1).

Example 2022-Phenethyl-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (504)

To a solution of the diamine 499 (73 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol). Theresulting solution is stirred for 10 min, then 3-phenylpropionic acidethyl ester (63 mg, 0.35 mmol) is added. The solution is heated at 80°C. for 2.5 h, then cooled to rt. The reaction mixture is quenched withsat. sodium bicarbonate solution (0.45 mL) andEtOAc:methanol:dichloromethane (1:1:5) is added, and the mixture isfiltered. The filtrate is evaporated, and the residue purified bychromatography on reversed phase silica gel; gradient elution withacetonitrile:water/0.1% TFA to give 17 mg of the product 504. ¹H NMR(DMSO-d₆) δ 10.81 (s, 1H), 10.74 (s, 1H), 8.27 (bs, 1H), 8.16 (bs, 1H),7.47-7.34 (m, 5H), 7.11-7.06 (m, 5H), 6.78 (m, 2H), 5.81 (d, 1H), 5.77(d, 1H), 3.17 (s, 4H); LC/MS: 2.45 min, m/z 328 (M⁺+1).

Example 2032-Methyl-cis-[5-phenyl-4-(pyridin-3-yl)]-4,5-dihydro-1H-imidazoleditrifluoroacetate (505)

To a solution of the diamine 499 (73 mg, 0.35 mmol) in toluene (1.2 mL)is added 2.0M trimethylaluminum in toluene (0.49 mL, 0.98 mmol). Theresulting solution is stirred for 10 min, then ethyl acetate (31 mg,0.35 mmol) is added. The solution is heated at 80° C. for 2.5 h, thencooled to rt. The reaction mixture is quenched with sat. sodiumbicarbonate solution (0.45 mL) and EtOAc:methanol:dichloromethane(1:1:5) is added, and the mixture is filtered. The filtrate isevaporated, and the residue purified by chromatography on reversed phasesilica gel; gradient elution with acetonitrile:water/0.1% TFA to give 74mg the product 505. ¹H NMR (CDCl₃) δ 8.10 (bs, 2H), 7.4 (bs, 3H), 7.2(m, 4H), 5.15 (bs, 2H), 2.55 (bs, 3H); LC/MS: 2.00 min, m/z 238 (M⁺+1).

Example 204

A mixture of cis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5) (5 mmol)in dichloromethane and p-nitrophenyl carbonate Wang resin (1 g, 1.32mmol/g) is shaken overnight, the resin filtered and washed withdichloromethane. A suspension of the monocarbamoylated resin (0.30 g,0.40 mmol) is treated with a substituted phenylacetic acid (1.2 mmol),1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 mmol) inDMF (6 mL), and the mixture is shaken overnight at rt. The resin isfiltered, washed with DMF, and the substituted phenylacetamidederivative is cleaved from the resin with 50% TFA/DMF at rt for 1.5 h.The solvents are evaporated, and the residue is dissolved intrimethylsilyl polyphosphate/dichloromethane solution (1:4), and thesolution is microwaved at 140° C. for 2×4 min to effect imidazoline ringformation. The mixture is diluted with dichloromethane, washed withwater, sat. sodium bicarbonate, brine, then dried (Na₂SO₄), andfiltered. The filtrate is rotary evaporated, and the residue purified bychromatography on silica gel; elution with acetonitrile:water/0.5% TFA(80:20) gives the product.

The compounds so prepared are summarized in Table 4, which are alsoidentified by a compound number. Also summarized in Table 4 are theamounts of the compound formed, the LC/MS retention time, m/e ion peak,and the substituted phenylacetic acid employed to make the respectivecompound.

TABLE 4 Compound Amount (mg) LC/MS retention time LC/MS m/z (M⁺ + 1). #Substituted phenylacetic acid 5352-(3-Chlorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 7 mg 2.85 min 383(3-chlorophenyl)acetic acid 5362-(3,4-Difluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 3 mg 2.83 min 385(3,4-difluorophenyl)acetic acid 5372-(2,4-Difluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 5 mg 2.80 min 385(2,4-difluorophenyl)acetic acid 5382-(4-Fluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 11 mg  2.76 min 367(4-fluorophenyl)acetic acid 5392-(2-Fluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole trifluoroacetate 6 mg 2.75 min 367(2-fluorophenyl)acetic acid

Example 205 Scheme 8, Method g

The procedure as set forth in Example 204 is essentially repeated inthis Example except that cis-1,2-diphenylpropane-1,2-diamine (16) (5mmol) is employed in the place ofcis-1,2-bis-(3-fluorophenyl)ethane-1,2-diamine (5) (5 mmol). Thesubstituted 3-phenylacetamide derivative so formed is then cleaved inaccordance with the procedures of Example 204 and the compound isisolated.

The compounds so prepared are summarized in Table 5, which are alsoidentified by a compound number. Also summarized in Table 5 are theamounts of the compound formed, the LC/MS retention time, m/e ion peak,and the substituted 3-phenylacetic acid employed to make the respectivecompound.

TABLE 5 Product Amount (mg) LC/MS retention time LC/MS m/z (M⁺ + 1). #Substituted phenylacetic acid 5402-(4-Fluorobenzyl)-cis-4,5-diphenyl-4-methyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 44 mg 2.86 min 345 (4-fluorophenyl)acetic acid 5412-(3,4-Difluorobenzyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole trifluoroacetate 29 mg 2.87 min 363(3,4-difluorophenyl)acetic acid 5422-(3-Chlorobenzyl)-cis-4,5-diphenyl-4-methyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 43 mg 2.89 min 361 (3-chlorophenyl)acetic acid 5432-(2,4-Difluorobenzyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole trifluoroacetate 23 mg 2.60 min 363(2,4-difluorophenyl)acetic acid 5442-(1-Phenyl-1-ethyl)-cis-4,5-diphenyl-4-methyl- 4,5-dihydro-1H-imidazoletrifluoroacetate 12 mg 2.84 min 341 2-phenyl-2-propionic acid 5452-[1-(4-Chlorophenyl)-1-ethyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole trifluoroacetate 14 mg 2.95 min 3752-(4-chlorophenyl)-2-propionic acid

Example 2062-(4-Fluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazoletrifluoroacetate (546)

A mixture of cis-1,2-bis-(3-fluorophenyl)propane-1,2-diamine (23) (5mmol) in dichloromethane and p-nitrophenyl carbonate Wang resin (1 g,1.32 mmol/g) is shaken overnight, the resin filtered and washed withdichloromethane. A suspension of the monocarbamoylated resin (0.30 g,0.40 mmol) is treated with (4-fluorophenyl)acetic acid (1.2 mmol),1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 mmol) inDMF (6 mL), and the mixture is shaken overnight at RT. The resin isfiltered, washed with DMF, and the substituted (4-fluorophenyl)acetamidederivative is cleaved from the resin with 50% TFA/DMF at rt for 1.5 h.The solvents are evaporated, and the residue is dissolved intrimethylsilyl polyphosphate/dichloromethane solution (1:4), and thesolution is microwaved at 140° C. for 2×4 min to effect imidazoline ringformation. The mixture is diluted with dichloromethane, washed withwater, sat. sodium bicarbonate, brine, then dried (Na₂SO₄), andfiltered. The filtrate is rotary evaporated, and the residue purified bychromatography on silica gel; elution with acetonitrile:water/0.5% TFA(80:20) gives 44 mg of the product; LC/MS: 3.02 min, m/z 381 (M⁺+1).

Example 2071-[(2-Methylthio)-cis-4,5-diphenyl-4,5-dihydro-imidazol-1-yl]ethanone(547)

To a solution of2-(methylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydroiodide(42) (1.00 g, 2.52 mmol), triethylamine (0.262 mL, 2.77 mmol),4-dimethylaminopyridine (20 mg) in dichloromethane (20 mL) is addedacetic anhydride (0.033 mL, 0.262 mmol), and the mixture is stirred atrt overnight. The reaction mixture is diluted with dichloromethane andwashed with water, brine, and the organic layer is dried (MgSO₄),filtered, and evaporated. The residue is purified by chromatography onsilica gel; elution with heptane:EtOAc (1:1) followed by evaporationgives a solid that is recrystallized from heptane:dichloromethane (95:5)to give 0.47 g of the product 547. ¹H NMR (CDCl₃) δ 7.10-6.90 (m, 8H),6.90-6.70 (m, 2H), 5.65 (d, 1H), 5.45 (d, 1H), 2.55 (s, 3H), 1.95 (s,3H); MS: m/z 311 (M⁺+1).

Example 2082-(Methylthio)-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acidphenyl ester (548)

To a solution of2-(methylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydroiodide(42) (1.00 mg, 2.52 mmol), triethylamine (0.528 mL, 0.379 mmol),4-dimethylamino-pyridine (10 mg) in dichloromethane (20 mL) is addedphenyl chloroformate (0.379 mL, 3.02 mmol), and the mixture is stirredat rt overnight. The reaction mixture is diluted with dichloromethaneand washed with water, brine, and the organic layer is dried (MgSO₄),filtered, and evaporated. The residue is purified by chromatography onsilica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 0.58g of the product 548. ¹H NMR (CDCl₃) δ 7.25-6.95 (m, 11H), 6.95-6.80 (m,2H), 6.80-6.70 (m, 2H), 5.80-5.65 (m, 2H), 2.62 (s, 3H). MS: m/z 389(M++1).

Example 2091-[2-(4-Fluorobenzylthio)-cis-4,5-diphenyl-4,5-dihydro-imidazol-1-yl]ethanone(549)

To a solution of2-[(4-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride (197) (0.50 g, 1.25 mmol), triethylamine (0.384 mL, 2.75mmol), 4-dimethylaminopyridine (20 mg) in dichloromethane (20 mL) isadded acetic anhydride (0.130 mL, 1.38 mmol), and the mixture is stirredat rt for 3 h. Additional acetic anhydride (0.100 mL, 1.06 mmol) isadded, and the mixture is stirred at rt overnight. The reaction mixtureis diluted with dichloromethane and washed with water, brine, and theorganic layer is dried (MgSO₄), filtered, and evaporated. The residue isrecrystallized from heptane:dichloromethane (95:5) to give 0.37 g of theproduct 549. ¹H NMR (CDCl₃) δ 7.60-7.40 (m, 2H), 7.10-6.90 (m, 8H),6.90-6.75 (m, 2H), 6.75-6.65 (m, 2H), 5.65 (d, 1H), 5.43 (d, 1H), 4.33(q, 2H), 1.91 (s, 3H). MS: m/z 405 (M⁺+1).

Example 2102-(Methoxy-phenyl-methyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate

Step 1.

One of the starting materials, methoxy-(S)-phenyl-acetic acid methylester is made from commercially available methyl-(S)-mandelate followingthe procedure set forth in Tetrahedron Letters 40 (1999) 1843-1846.

Step 2:

Employing the general trimethylaluminum coupling procedure and usingmethoxy-(S)-phenyl-acetic acid methyl ester prepared in accordance withStep 1 as described above and meso-1,2-diphenylethylene-diamine therewas made,2-(Methoxy-phenyl-methyl)-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate. ¹H NMR (DMSO) δ 11.11 (bs, 1 H), 7.7-7.5 (m, 5 H),7.1-7.0 (m, 6 H), 6.90-6.85 (m, 2 H), 6.8-6.7 (m, 2 H), 5.81 (s, 2 H),5.65 (s, 1 H), 3.49 (s, 3 H); LC/MS: 3.69 min, m/z 343 (M⁺+1)

Example 211(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanoltrifluoroacetate

Step 1:

(tert-Butyl-dimethyl-silanyloxy)-phenyl-acetic acid methyl ester

To a solution of commercially available methyl (S)-mandelate (2.39 g,14.4 mmol) in dichloromethane (50 mL) is added imidazole (1.18 g, 17.3mmol), tert-butyldimethylsilyl chloride (2.38 g, 15.8 mmol) and4-dimethylaminopyridine (176 mg, 1.44 mmol). The mixture is stirred for16 hrs then diluted with ether, washed with water, brine, then dried(MgSO₄), filtered and concentrated. The residue is purified bychromatography on silica gel; elution with EtOAc:heptane (25:75) gives3.67 g of the product. ¹H NMR (CDCl₃) δ 7.45-7.40 (m, 2 H), 7.35-7.25(m, 3 H), 5.20 (s, 1 H), 3.65 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 3 H),0.05 (s, 3 H); MS: m/z 281 (M⁺+1)

Step 2:

Employing the general trimethylaluminum coupling procedure and using(tert-butyl-dimethyl-silanyloxy)-phenyl-acetic acid methyl esterprepared in accordance with the procedures set out in Step 1 above andmeso-1,2-diphenylethylene-diamine there is made:(4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanoltrifluoroacetate. ¹H NMR (DMSO) δ 10.95 (bs, 2 H), 7.70-7.67 (m, 2 H),7.57-7.46 (m, 3 H), 7.2-7.0 (m, 7 H), 6.9-6.8 (m, 4 H), 5.88 (s, 1 H),5.77 (s, 2 H); LC/MS: 2.39 min, m/z 329 (M⁺+1)

Example 212 Phenyl-carbamic acid(cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methyl estertrifluoroacetate

Step 1:

To a solution of(4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanol (231 mg,0.70 mmol) in dichloromethane (2.4 mL) is added phenyl isocyanate (91μL, 0.84 mmol) and 4-dimethylaminopyridine (8 mg, 0.07 mmol). Themixture is stirred for 2 hrs then concentrated. The residue is purifiedby chromatography on silica gel; eluting with MeOH:CH₂CL₂ (3:97). Theresidue is further purified by chromatography on reverse phase silicagel; gradient elution with acetonitrile/0.1% TFA:water/0.1% TFA (45:55to 85:15 over 20 min) gives 19 mg of product. ¹H NMR (DMSO) δ 10.95 (bs,2 H), 7.78 (bs, 1 H), 7.70-7.63 (m, 2 H), 7.6-7.4 (m, 4 H), 7.2-7.0 (m,7 H), 6.85-6.80 (m, 4 H), 6.75-6.60 (m, 3 H), 5.86 (s, 1 H), 5.77 (s, 2H); LC/MS: 2.95 min, m/z 448 (M⁺+1).

A few of the trans-isomeric form of the compounds of the presentinvention are prepared in the following Comparative Examples 1 to 20 inorder to test their efficacy in inhibiting the effects of P2X7 receptorsite in accordance with the procedures set forth in Example 214. Theresults obtained indicate that the following trans-isomers are notactive in inhibiting the effects of P2X7 receptor.

Comparative Example 1[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2-chlorobenzyl)amine(166)

A mixture of intermediate 70 (300 mg, 0.814 mmol), 2-chlorobenzylamine(0.5 mL, 4.14 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 102 mg of the product 166. LC/MS: 1.41 min, m/z 362(M⁺+1).

Comparative Example 2[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2-trifluoromethylbenzyl)-amine(167)

A mixture of intermediate 70 (300 mg, 0.814 mmol),2-trifluoromethylbenzylamine (0.5 mL, 3.57 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 160 mg of the product 167. LC/MS:1.79 min, m/z 396 (M⁺+1).

Comparative Example 3[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2,4-dichlorobenzyl)amine(168)

A mixture of intermediate 70 (300 mg, 0.814 mmol),2,4-dichlorobenzylamine (0.5 mL, 3.74 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 170 mg of the product 168. LC/MS:1.46 min, m/z 396 (M⁺+1).

Comparative Example 4[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(3,4-dichlorobenzyl)amine(169)

A mixture of intermediate 70 (300 mg, 0.814 mmol),3,4-dichlorobenzylamine (0.5 mL, 3.77 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to RT. Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 170 mg of the product 169. LC/MS:1.82 min, m/z 396 (M⁺+1).

Comparative Example 5[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(3-methoxybenzyl)amine(170)

A mixture of intermediate 70 (300 mg, 0.814 mmol), 3-methoxybenzylamine(0.5 mL, 3.83 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 129 mg of the product 170. LC/MS: 1.38 min, m/z 358(M⁺+1).

Comparative Example 6[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(4-trifluoromethylbenzyl)-amine(171)

A mixture of intermediate 70 (300 mg, 0.814 mmol),4-trifluoromethylbenzylamine (0.5 mL, 3.51 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 69 mg of the product 171. LC/MS:1.81 min, m/z 396 (M⁺+1).

Comparative Example 7[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(3,4,5-trimethoxybenzyl)-amine(172)

A mixture of intermediate 70 (300 mg, 0.814 mmol),3,4,5-trimethoxybenzylamine (0.5 mL, 2.93 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 144 mg of the product 172. LC/MS:1.36 min, m/z 418 (M⁺+1).

Comparative Example 8[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)amine(173)

A mixture of intermediate 70 (300 mg, 0.814 mmol), 4-fluorobenzylamine(0.5 mL, 4.40 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 102 mg of the product 173. LC/MS: 1.39 min, m/z 346(M⁺+1).

Comparative Example 9[trans-(4S,5S)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]aminetrifluoroacetate (174)

A mixture of intermediate 70 (500 mg, 1.36 mmol) in ethylene glycol (3.5mL) is saturated with ammonia and heated at 170° C. overnight. Thereaction mixture is cooled to rt, and water added. The precipitatedmaterial is filtered and purified by preparative HPLC to give 160 mg ofthe product 174. ¹H NMR (CDCl₃) δ 8.39 (s, 2 H), 8.15 (s, 2 H),7.50-7.25 (m, 6 H), 7.25-7.10 (m, 4 H), 4.76 (s, 2 H); LC/MS: 2.78 m/z238 (M⁺+1).

Comparative Example 10[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2-trifluoromethylbenzyl)-amine(175)

A mixture of intermediate 71 (300 mg, 0.814 mmol),2-trifluoromethylbenzylamine (0.5 mL, 3.57 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 124 mg of the product 175. LC/MS:1.79 min, m/z 396 (M⁺+1).

Comparative Example 11[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2,4-dichlorobenzyl)amine(176)

A mixture of intermediate 71 (300 mg, 0.814 mmol),2,4-dichlorobenzylamine (0.5 mL, 3.74 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 107 mg of the product 176. LC/MS:1.81 min, m/z 396 (M⁺+1).

Comparative Example 12[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(3,4-dichlorobenzyl)amine(177)

A mixture of intermediate 71 (300 mg, 0.814 mmol),3,4-dichlorobenzylamine (0.5 mL, 3.77 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 275 mg of the product 177. LC/MS:1.47 min, m/z 396 (M⁺+1).

Comparative Example 13[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2-methoxybenzyl)amine(178)

A mixture of intermediate 71 (300 mg, 0.814 mmol), 2-methoxybenzylamine(0.5 mL, 3.83 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 94 mg of the product 178. LC/MS: 1.40 min, m/z 358(M⁺+1).

Comparative Example 14[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(3-methoxybenzyl)amine(179)

A mixture of intermediate 71 (300 mg, 0.814 mmol), 3-methoxybenzylamine(0.5 mL, 3.83 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 172 mg of the product 179. LC/MS: 1.39 min, m/z 358(M⁺+1).

Comparative Example 15[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(4-trifluoromethylbenzyl)-amine(180)

A mixture of intermediate 71 (300 mg, 0.814 mmol),4-trifluoromethylbenzylamine (0.5 mL, 3.51 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 166 mg of the product 180. LC/MS:1.45 min, m/z 396 (M⁺+1).

Comparative Example 16[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(2-fluorobenzyl)amine(181)

A mixture of intermediate 71 (300 mg, 0.814 mmol), 2-fluorobenzylamine(0.5 mL, 4.37 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 105 mg of the product 181. LC/MS: 1.38 min, m/z 346(M⁺+1).

Comparative Example 17[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(3,4,5-trimethoxybenzyl)-amine(182)

A mixture of intermediate 71 (300 mg, 0.814 mmol),3,4,5-trimethoxybenzylamine (0.5 mL, 2.93 mmol) is heated at 150° C.(reaction block) overnight. The reaction mixture is cooled to rt, Thecorresponding N-Boc intermediate is not isolated. The reaction mixtureis dissolved in EtOAc (10 mL) and hydrogen chloride is bubbled into thesolution for 1 min, and the solution is stirred at rt overnight. Thereaction mixture is neutralized, the solvent is evaporated, and theresidue is purified by chromatography on silica gel; gradient elutionwith heptane:EtOAc (70:30-50:50) gives 144 mg of the product 182. LC/MS:1.36 min, m/z 418 (M⁺+1).

Comparative Example 18[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-(4-fluorobenzyl)amine(183)

A mixture of intermediate 71 (300 mg, 0.814 mmol), 4-fluorobenzylamine(0.5 mL, 4.40 mmol) is heated at 150° C. (reaction block) overnight. Thereaction mixture is cooled to rt, The corresponding N-Boc intermediateis not isolated. The reaction mixture is dissolved in EtOAc (10 mL) andhydrogen chloride is bubbled into the solution for 1 min, and thesolution is stirred at rt overnight. The reaction mixture isneutralized, the solvent is evaporated, and the residue is purified bychromatography on silica gel; gradient elution with heptane:EtOAc(70:30-50:50) gives 155 mg of the product 183. LC/MS: 1.72 min, m/z 346(M⁺+1).

Comparative Example 19[trans-(4R,5R)-Diphenyl-4,5-dihydro-1H-imidazol-2-yl]-aminetrifluoroacetate (184)

A mixture of intermediate 71 (500 mg, 1.36 mmol) in ethylene glycol (3.5mL) is saturated with ammonia and heated at 130° C. overnight. Thereaction mixture is cooled to rt, and water added. The precipitatedmaterial is filtered and purified by preparative HPLC to give 136 mg ofthe product 184. ¹H NMR (CDCl₃) δ 8.38 (s, 2 H), 8.20 (s, 2 H),7.50-7.30 (m, 6 H), 7.30-7.15 (m, 4 H), 4.78 (s, 2 H); LC/MS: 2.82 m/z238 (M⁺+1).

Comparative Example 20trans-4,5-bis-(4-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-(4-fluoro-benzyl)amine(187)

A mixture of intermediate 74 (198 mg, 0.473 mmol), 4-fluorobenzylamine(0.5 mL, 4.2 mmol) is heated at 150° C. overnight. The reaction mixtureis cooled to rt, The reaction mixture is diluted with dichloromethane,washed with 3M HCl, brine, and then dried (MgSO₄). The mixture isfiltered, the filtrate evaporated, and the residue triturated withdichloromethane:Et₂O:heptane, and the insoluble material filtered togive 150 mg of the product 187. ¹H NMR (DMSO-d₆) δ 9.80-8.40 (m, 2 H),7.65-7.40 (m, 4 H), 7.40-7.10 (m, 8 H), 7.15-6.80 (m, 8 H), 4.98 (s, 1H), 4.70-4.40 (m, 2 H), 1.10 (s, 3 H); MS: m/z 396 (M⁺+1).

BIOLOGICAL EXAMPLES Example 213

This Example illustrates the biological efficacy of the compounds of thepresent invention at the P2X7 receptor site.

A human analog of the rat P2X7 clone (Suprenant et al., “The cytolyticP2Z receptor for extracellular ATP identified as a P2X receptor (P2X7),”Science vol. 272, May 3, 1996, pp. 735-738.) was identified by a BLASTsearch of the database maintained by Incyte Pharmaceuticals, Inc. (PaloAlto, Calif.). The complete open reading frame of human P2X7 wasamplified from Incyte clone 148057 with the polymerase chain reactionusing an upstream primer B299(5′-GGTACCAAGCTTGAGTCACCATGCCGGCCTGCTGCAG-3′) containing the initiatingmethionine codon and a downstream primer (M13 reverse). Restriction ofthe pcr product at the Hin dIII site and at the vector-derived Kpn Isite produced a 2177 bp DNA suitable for cloning into the eukaryoticexpression vector pcDNA3 (Stratagene). The DNA sequence of the humanP2X7 cDNA was determined in its entirety; the deduced peptide sequencewas identical to that submitted to GENBANK under the accession numberY09561. This inferred protein contains 595 amino acids and has acalculated MW of 68,558 Da.

U373 cells were transfected with pcDNA3-P2X7 using the calcium phosphateco-precipitation technique and grown in Dulbecco's modified Eagle'smedium supplemented with 10% fetal bovine serum at 37° C. in anatmosphere of 95% air, 5% CO₂. Following a 24-hr exposure to DNA, cellswere trypsinized and re-seeded at low density in the presence of 600 mMG418. After incubation for 2 weeks, isolated clones were selected withcloning cylinders and replated in 200 mM G418. Cell clones were thenexpanded. Clones were screened for P2X7 by applying ATP and recordingthe resultant current using patch clamp electrophysiology.

U373 cells stably expressing P2X7 were used to screen drugs via a dyeuptake assay. Cells were plated overnight on collagen coated 96-wellplates at a density of 35,000 cells per well. The following day, culturemedia was replaced with Mg⁺⁺ and Ca⁺⁺-free Hank's balanced salt solutionand various concentrations of test compounds ranging from 30 nM to 3 μM.Cells were then allowed to incubate with test compounds at 37° C. for 20minutes. Following this incubation period YO-PRO-1 dye (MolecularProbes, Eugene, Oreg., final concentration 5 μM) and 2′-&3′-O-(4-Benzolybenzoyl)-Adenosine 5′-triphosphate (Sigma Chemical, StLouis, Mo., final concentration 300 μM) were added to the cellssequentially. Cells were then incubated at 37° C. for 1.5 hours. Afterthis period, cellular fluorescence (indicating dye uptake through P2X7)was measured using a fluorescence plate reader (excitation: 485/20,emission: 530/25). Fluorescence in the presence of test substances wascompared to that in the absence of test substances (control). These datawere expressed as a % of control and plotted against concentration todetermine IC₅₀ values and are summarized in Table 6.

TABLE 6 Compound IC₅₀ (nM)(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)benzylamine hydrochloride135 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)- 124(cyclohexylmethyl)amine hydrochloride(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-N- 147 methylbenzylaminehydrochloride (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4,5- 77trifluorobenzyl)amine hydrochloride(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4- 96fluorobenzyl)amine hydrochloride(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3- 89fluorobenzyl)amine hydrochloride(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,5- 102difluorobenzyl)amine hydrochloride(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-[2-(2- 87fluorophenyl)ethyl]amine hydrochloride(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-2-phenethylaminehydrochloride 113(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-methylbenzyl)amine187(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4-difluorobenzyl)amine65 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-chlorobenzyl)amine164 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-bromobenzyl)amine225 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-bromobenzyl)amine503(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-methylbenzyl)amine243(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-chloro-4-fluorobenzyl)amine247(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-[2-(4-fluorophenyl)ethyl]amine331(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2-chlorobenzyl)amine587(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3,4-dichlorobenzyl)amine307(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2,4-difluorobenzyl)amine289 (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2- 409fluorobenzyl)amine (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-471 chlorobenzyl)amine(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(2- 409methoxybenzyl)amine (cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(3-386 methoxybenzyl)amine(cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl)-benzylaminehydrochloride 531(cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl)-(4- 390fluorobenzyl)amine hydrochloride[cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 312difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(2-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 379methylbenzyl)amine hydrochloride[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]- 90benzylamine hydrochloride[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 42fluorobenzyl)amine hydrochloride[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 71fluorobenzyl)amine hydrochloride[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 71difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]- 167benzylamine hydrochloride[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 121fluorobenzyl)amine hydrochloride[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 139fluorobenzyl)amine hydrochloride[cis-4,5-bis-(2-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 77difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]- 157benzylamine hydrochloride[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 121fluorobenzyl)amine hydrochloride[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 107fluorobenzyl)amine hydrochloride[cis-4,5-bis-(3-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 118difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]- 275benzylamine hydrochloride[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 134fluorobenzyl)amine hydrochloride[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 287fluorobenzyl)amine hydrochloride[cis-4,5-bis-(4-Methylphenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 150difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(3-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]- 433benzylamine hydrochloride[cis-4,5-bis-(3-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 318fluorobenzyl)amine hydrochloride[cis-4,5-bis-(3-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 247difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]- 925benzylamine hydrochloride[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 592fluorobenzyl)amine hydrochloride[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 624fluorobenzyl)amine hydrochloride[cis-4,5-bis-(2-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 378difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(4-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]- 404benzylamine hydrochloride[cis-4,5-bis-(4-Chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3,4- 400difluorobenzyl)-amine hydrochloride[cis-4,5-bis-(2-Bromophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(3- 782fluorobenzyl)amine hydrochloride[cis-4,5-bis-(2-Bromophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 898fluorobenzyl)amine hydrochloride[cis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]- 371benzylamine hydrochloridecis-4,5-bis-(4-Fluorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-(4- 338fluorobenzyl)amine hydrochloride(cis-4,5-Diphenyl-4-methyl-4,5-dihydro-1H-imidazol-2-yl)-(4- 63fluorobenzyl)amine hydrochloride[4,5-cis-bis-(4-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-139 (4-fluoro-benzyl)aminecis-4,5-bis-(3-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]- 37(4-fluoro-benzyl)amine2-[(4-Fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 300hydrochloride 2-(Benzylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole214 hydrochloride2-[(3-Chlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 634hydrochloride2-[(2-Chlorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 630hydrochloride2-[(2-Fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 819hydrochloride2-[(3-Methylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 722hydrochloride2-[(3,4-Difluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H- 461imidazole hydrochloride2-[(3-Methoxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 987hydrochloride2-[(3-Fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 240hydrochloride2-[(2-Iodobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 647hydrochloride2-[(3,4-Dibenzyloxybenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H- 548imidazole hydrochloride2-[(2-Methylbenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 449hydrochloride2-[(2-Chloro-4-fluorobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H- 828imidazole hydrochloride2-[(2-Bromobenzyl)thio]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 521hydrochloride 2-Phenethyl-cis-4,5-diphenyl-4,5-dihydro-1H-imidazolehydrochloride 772-Phenethyl-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H-imidazole 146hydrochloride2-Phenethyl-cis-4,5-bis-(4-fluorophenyl)-4,5-dihydro-1H-imidazole 277hydrochloride2-Phenethyl-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H-imidazole 22hydrochloride2-Phenethyl-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydro-1H- 66imidazole hydrochloride2-[2-(3,4-Difluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5- 173dihydro-1H-imidazole2-[2-(2-Chlorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-140 1H-imidazole2-(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1-phenylethan-1-ol 1952-[2-(2-Methoxyphenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 832imidazole trifluoroacetate2-[2-(2-Methylphenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 42imidazole2-[2-(3,4-Difluorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 122imidazole2-[2-[(2S)-Phenyl)propyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 13trifluoroacetate2-[2-(2-Fluorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole164 trifluoroacetate2-[2-(3-Fluorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 31trifluoroacetate2-[2-(4-Fluorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole218 trifluoroacetate2-[2-(2-Chlorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 48imidazole trifluoroacetate2-[2-(3-Methylphenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 229imidazole trifluoroacetate2-(3-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 34trifluoroacetate2-(4-Trifluoromethylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 403imidazole trifluoroacetate2-(2-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 577trifluoroacetate2-(4-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 46trifluoroacetate2-(2-Bromobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 321trifluoroacetate2-(2,4-Difluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 42trifluoroacetate2-(3,4-Difluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 24trifluoroacetate2-(2-Methylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 321trifluoroacetate2-[(1-Phenyl)-(1S)-ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 110trifluoroacetate2-[(1-Phenyl)-(1R)-ethyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 108trifluoroacetate2-[1-{(4-Chlorophenyl)-1-methyl}ethyl)-cis-4,5-diphenyl-4,5-dihydro- 5371H-imidazole trifluoroacetate2-[1-Phenyl-1-cyclopropyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 334trifluoroacetate2-[1-(4-Chlorophenyl)-1-ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 423imidazole trifluoroacetate2-(2-Chloro-6-fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 826imidazole trifluoroacetate2-(4-Methylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 83trifluoroacetate2-(2-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 163trifluoroacetate2-(2,5-Difluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 142trifluoroacetate2-(2,6-Difluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 966trifluoroacetate2-(3-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 84trifluoroacetate2-(3-Methylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 376trifluoroacetate2-(2,3-Difluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 930trifluoroacetate2-(4-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 269trifluoroacetate2-(2-Chloro-4-fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 120imidazole trifluoroacetate2-(3-Fluoro-4-methylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 178imidazole trifluoroacetate2-(3-Chloro-4-fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 13imidazole trifluoroacetate2-(2-Fluoro-3-chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 142imidazole trifluoroacetate2-(2,6-Difluoro-3-methylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 594imidazole trifluoroacetate2-(2-Methyl-5-fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H- 319imidazole trifluoroacetate2-[2-(2-Fluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-304 1H-imidazole trifluoroacetate2-[2-(3-Fluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro- 791H-imidazole trifluoroacetate2-[2-(4-Fluorophenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-572 1H-imidazole trifluoroacetate2-[2-(3-Methylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-385 1H-imidazole trifluoroacetate2-[2-(2-Methylphenyl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro- 941H-imidazole trifluoroacetate2-[(2-Thiophen-2-yl)ethyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro- 5921H-imidazole trifluoroacetate2-[(cis-4,5-Diphenyl-4,5-dihydro1H-imidazol-2-yl)-2-ethyl]pyridine 720[4,5-cis-bis-(3-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]- 49(3-fluoro-benzyl)amine[4,5-cis-bis-(4-Fluorophenyl)-4-methyl-4,5-dihydro-1H-imidazol-2-yl]-353 (3-fluoro-benzyl)amine2-[(Phenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 6122-[(3-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 224imidazole trifluoroacetate2-[(4-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 401imidazole trifluoroacetate2-[(Benzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 3252-[(3-Fluorobenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 274imidazole hydrochloride2-[(3-Methylbenzyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 415imidazole hydrochloride2-[(Phenylsulfanyl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 198trifluoroacetate2-[(Benzylsulfanyl)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 583trifluoroacetate2-[(Cyclohexyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 315trifluoroacetate2-[(Cycloheptyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 603imidazole trifluoroacetate2-[(Cyclooctyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 506trifluoroacetate[(cis-4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)methyl]benzylamine 318ditrifluoroacetate2-[(2-Phenethyloxy)methyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 768imidazole2-[(2-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-834 1H-imidazole2-[(3-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-316 1H-imidazole2-[(4-Fluorophenoxy)methyl]-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-346 1H-imidazole2-[(Phenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 405imidazole trifluoroacetate2-[(3-Fluorophenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro- 1041H-imidazole trifluoroacetate2-(Cyclohexylmethoxy)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 275imidazole trifluoroacetate2-[(Benzylsulfanyl)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 525imidazole2-[(Cyclopentyloxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro- 4871H-imidazole hydrochloride2-[(1-Ethynyl-1-butoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5- 739dihydro-1H-imidazole hydrochloride2-[(Cyclopentylmethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5- 194dihydro-1H-imidazole hydrochloride2-[(1-Cyclopentyl-1-ethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5- 160dihydro-1H-imidazole hydrochloride2-[[(Cyclopropyl)methoxy]methyl]-cis-4,5-diphenyl-4-methyl-4,5- 676dihydro-1H-imidazole trifluoroacetate2-[(2-Chlorophenoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro- 7431H-imidazole hydrochloride2-(1-Phenoxyethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 356imidazole trifluoroacetate2-[(Cyclobutoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 722imidazole trifluoroacetate2-[(1-Cyclopropyl-1-ethoxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5- 397dihydro-1H-imidazole trifluoroacetate2-[(1-Benzopyran-4-yloxy)methyl]-cis-4,5-diphenyl-4-methyl-4,5- 490dihydro-1H-imidazoline hydrochloride2-Phenylthiomethyl-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H- 866imidazole ditrifluoroacetate2-Phenethyl-cis-4-phenyl-5-(pyridin-3-yl)-4,5-dihydro-1H-imidazole 251ditrifluoroacetate2-(3-Chlorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H- 330imidazole trifluoroacetate2-(3,4-Difluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H- 79imidazole trifluoroacetate2-(2,4-Difluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H- 409imidazole trifluoroacetate2-(4-Fluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H- 217imidazole trifluoroacetate2-(2-Fluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4,5-dihydro-1H- 449imidazole trifluoroacetate2-(4-Fluorobenzyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 44imidazole trifluoroacetate2-(3,4-Difluorobenzyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 19imidazole trifluoroacetate2-(3-Chlorobenzyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 42imidazole trifluoroacetate2-(2,4-Difluorobenzyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 16imidazole trifluoroacetate2-(1-Phenyl-1-ethyl)-cis-4,5-diphenyl-4-methyl-4,5-dihydro-1H- 68imidazole trifluoroacetate2-[1-(4-Chlorophenyl)-1-ethyl]-cis-4,5-diphenyl-4-methyl-4,5-dihydro-331 1H-imidazole trifluoroacetate2-(4-Fluorobenzyl)-cis-4,5-bis-(3-fluorophenyl)-4-methyl-4,5-dihydro- 321H-imidazole trifluoroacetate2-(Methoxy-phenyl-methyl)-4,5-diphenyl-4,5-dihydro-1H-imidazole 101trifluoroacetate(4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanol 241trifluoroacetate Phenyl-carbamic acid(4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)- 625 phenyl-methyl estertrifluoroacetate2-[2-Methyl-(2S)-phenyl)-propyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 10imidazole trifluoroacetate2-[2,2-Diphenylethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 320trifluoroacetate2-[1-Methyl-2-phenylethyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 570trifluoroacetate2-[3-Phenyl-propyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 540trifluoroacetate2-[4-Phenyl-butyl]-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 610trifluoroacetate2-[2-(3-Chlorophenyl)ethyl]-cis-4,5-diphenyl-4,5-dihydro-1H- 120imidazole trifluoroacetate2-(2-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 160trifluoroacetate2-(4-Chlorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 270trifluoroacetate2-(3-Fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 80trifluoroacetate2-(2,3-Difluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 930trifluoroacetate2-(4-Methylbenzyl)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 80trifluoroacetate2-Indan-2-ylmethyl-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole 240trifluoroacetate 2-Indan-2-yl-4,5-diphenyl-4,5-dihydro-1H-imidazoletrifluoroacetate 50

Example 214

This Example demonstrates that the compounds of this invention areeffective in inhibiting P2X7-mediated release of IL-1β from humanmacrophages activated by the Alzheimer's beta amyloid peptide 1-42.

Cell isolation: Monocytes were isolated from peripheral bloodmononuclear cells (PBMCs) as follows. Whole blood was layered directlyonto Histopak 1077-1 columns (Sigma Biochemicals) and centrifuged at800×g for 15 minutes. The PBMC band of cells was removed to a fresh 50ml culture tube and diluted 1:1 with wash buffer (Phosphate bufferedsaline, pH 7.4 containing 2 mM EDTA and 5 mg/ml BSA) followed bycentrifugation at 800×g for 5 minutes. Cells were then washed bysequential resuspension of the cell pellet in wash buffer andcentrifugation at 600×g for 5 minutes. The wash process was repeateduntil the supernatant was clear of contaminating platelets (5 to 6washes). Monocytes were then purified from the PBMCs by negativeselection using a monocyte isolation kit (Miltenyi Biotec, Inc) thatcontains antibodies to non-monocytic cells, running the cells over amagnetic column to remove antibody-bound cells, and collecting the flowthrough volume of monocytes. Monocytes were washed once with wash bufferand seeded at 10E5 cells per well in 100 μl serum-free RPMI 1640 in96-well plates and incubated for 1 hour at 37° C. in a 5% CO₂/95%humidified tissue culture incubator. After 1 hour, the medium wasreplaced with 100 μl complete culture medium (RPMI 1640, 10% humanserum-type AB (heat inactivated), 25 mM HEPES, 2 mM glutamine, 50 U/mleach of penicillin and streptomycin) and incubated overnight (16 hours).Dosing regimen: The next day, the culture medium was replaced with 100μl fresh complete culture medium in the absence or presence of humanbeta amyloid 1-42 peptide (5 μM) and incubated at 37° C. in a 5% CO₂/95%humidified tissue culture incubator for 5 hours. Medium was then removedand discarded. Each well was washed once with Hanks buffered saline(HBSS) containing 1 mM CaCl₂ followed by the addition of 80 μl ofHBSS/CaCl₂. Samples were then given either 10 μl of HBSS/CaCl₂ or 10 μlof the P2X7 inhibiting compound of the present invention (10× stock inHBSS/CaCl₂ for a final concentration of 23 nM and 206 nM) and incubated15 minutes in the tissue culture incubator followed by the addition ofeither 10 μl of HBSS/CaCl₂ or 10 μl of benzoyl ATP (BzATP; 3 mM stock inHBSS/CaCl₂ for a 300 μM final concentration) and incubated for a further30 minutes in the tissue culture incubator. Medium was then removed tonew 96-well plates for storage at −70° C. until the IL-1β content wasquantitated by ELISA (from R&D Systems). The cells were washed once withHBSS/CaCl₂ followed by lysing the cells with 100 μl ice cold lysisbuffer (100 mM Tris, pH 7.6, 1% triton X-100, and 1 tablet per 30 mlComplete TM protease inhibitor from Roche Biochemicals, Inc). Celllysates were stored at −70° C. until the IL-1β was quantitated by ELISA.

The results thus obtained for percent inhibition of BzATP-induced IL-1βsecretion using a few of the P2X-7 compounds of the present inventionare summarized in Table 7.

TABLE 7 Compound IC₅₀ (nM)2-(3-Chloro-4-fluorobenzyl)-cis-4,5-diphenyl-4,5-dihydro- 1571H-imidazole trifluoroacetate2-(2-Methyl-2-phenyl-propyl)-4,5-diphenyl-4,5-dihydro-1H- 178 imidazoletrifluoroacetate[cis-4,5-bis-(3-Fluorophenyl)-4,5-dihydro-1H-imidazol-2- 1276yl]-(3-fluorobenzyl)amine hydrochloride(4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluoro- 693 benzyl)-aminehydrochloride

Example 215

This example illustrates the efficacy of the compounds of this inventionin the treatment of multiple sclerosis. As described herein,experimental autoimmune encephalomyelitis (EAE) model is used to showsuch an efficacy. The following procedures are employed in this model.

Animals:

SJL/J female mice, 8 wks. old, are obtained from Jackson Laboratories.

Antigens:

Myelin Proteolipid Protein (PLP 139-151) (HSLGKWLGHPDKF) (Cat # H-2478)is obtained from BACHEM, Bioscience, Inc., 3700 Horizon Dr., King ofPrussia, Pa. 19406, 1-610-239-0300 (phone), 1-610-239-0800 (fax).

Complete Freund's Adjuvant H37 Ra [1 mg/ml Mycobacterium TuberculosisH37 Ra] is obtained from Difco 1-800-521-0851 (Cat # 3114-60-5, 6×10ml).

Mycobacterium Tuberculosis is also obtained from Difco, 1-800-521-0851(Cat # 3114-33-8, 6×100 mg).

Pertussis Toxin

Bordetella Pertussis, (Lyophilized powder containing PBS and lactose) isobtained from List Biological Laboratories, 1-408-866-6363 (Product#180, 50 ug @ $140.00 ea.).

Induction of EAE in Mice

PLP139-151 peptide is dissolved in H₂O:PBS (1:1) solution to aconcentration 7.5 mg/10 ml (for 75 μg PLP per group) and emulsified withan equal volume of CFA supplemented with 40 mg/10 ml heated-killedmycobacterium tuberculosis H37Ra. Mice are injected s.c. with 0.2 ml ofpeptide emulsion in the abdominal flank (0.1 ml on each side). On thesame day and 72 hours later, mice are injected i.v. with 100 μl of 35 ngand 50 ng of Bordetella Pertussis toxin in saline respectively.

Clinical Assessment

-   STAGE 0: Normal-   STAGE 0.5: Partial limp tail-   STAGE 1: Complete Limp Tail-   STAGE 2: Impaired righting reflex-   STAGE 2.5: Righting reflex is delayed (Not weak enough to be stage    3).-   STAGE 3: Partial hind limb paralysis-   STAGE 3.5: One leg is completely paralyzed, and one leg is partially    paralyzed,-   STAGE 4: Complete hind limb paralysis-   STAGE 4.5: Legs are completely paralyzed and Moribund-   STAGE 5: Death due to EAE    Clinical Courses of EAE-   Acute phase: First clinical episode (Day 10-18)-   Remission: Phase of clinical improvement following a clinical    episode; characterized by a reduction (>=one grade) in clinical    score for at least two days after the peak score of acute phase or a    disease relapse.-   Relapse: Increase of at least one grade in clinical score for at    least two days after remission has been attained.

The animals treated with the compounds of this invention generally wouldbe expected to show improvements in clinical scores.

Example 216

This Example illustrates the efficacy of the compounds of the presentinvention for the treatment of stroke using an animal model.

Male Sprague Dawley rats (Charles River) weighing 280-320 g are givenfree access to food and water and acclimatized for a minimum of 4 daysbefore use in experiments.

All rats for use in studies are to be fasted beginning at 3:00 pm theday prior to surgery but given free access to water. Prior to surgeryeach rat is weighed. The rat is initially induced with 5% isoflurane(Aerrane, Fort Dodge), combined with 30% O₂, 70% N₂O for 2-5 minutes.The rat is then placed on a circulating water-heating pad and into anose cone for spontaneous respiration of anesthetic gases. Theisoflurane is reduced to 2%. A rectal probe is inserted and bodytemperature maintained at 36.5-37.5° C. The hair is clipped at allsurgical sites and these regions will then be scrubbed with Betadine.

Surgical procedure

-   -   A temporalis muscle probe is placed into the right temporalis        muscle and “brain” temperature” is monitored.    -   A midline neck incision is made in the upper thorax of the rat.        Careful dissection, isolation and retraction of the        sternomastoideus, digastricus, and sternohyoideus muscles is        made to expose the right common, internal and external carotid        arteries.    -   The right common carotid artery is isolated with a 5-0 silk        suture. During surgery the suture is released allowing        reperfusion every 2-4 minutes.    -   The right external carotid and superior thyroid arteries are        also isolated and the superior thyroid is cauterized, while the        external carotid is ligated distally with a 5-0 silk suture.        Another 5-0 silk suture is loosely tied around the external        carotid artery.    -   The occipital artery is isolated, ligated and incised.    -   The internal carotid is isolated.    -   With the common and external carotid arteries immobilized, an        aneurysm clip is placed onto the internal carotid artery.    -   A small incision is made at the distal end of the external        carotid.    -   A 3-0 nylon suture coated with poly-L-lysine is then inserted        into the external carotid and up into the common carotid artery.    -   The loosely tied 5-0 silk suture around the external carotid is        now gently tightened around the filament.    -   The external carotid artery is then incised and the remaining        piece of the external carotid artery with the filament is        rotated so that the filament may be inserted into the internal        carotid artery the length of insertion depending on the weight        and rat strain. In Sprague Dawley rats the monofilament is        inserted 18-19 mm (18 mm for rats weighing <300 gm, 19 mm for        rats weighing ≧300 gm) effectively blocking blood flow to the        middle cerebral artery.    -   The external jugular vein will be cannulated with PE 50 tubing        for I.V. administration of compounds. The cannula will be        exteriorized at the previously shaven, scruff of the neck and        sutured in place. The wound will be closed by means of suture.    -   The right femoral artery is catheterized for blood gas and        glucose determination during surgery.    -   Two hours after the insertion of the monofilament suture the        rats are re-anesthetized with the same anesthetic combination        used initially and placed back into the nose cone with the        reduction of isoflurane concentration to 2%.    -   The neck incision is reopened to expose the external carotid        artery.    -   The restoration of blood flow is accomplished by completely        withdrawing the intraluminal suture from the carotid arteries.    -   The incision is then closed with 3-0 silk in an interrupted        stitch        Compound Administration        Five groups of 15 animals are subjected to the above        methodology.    -   Compounds are infused (I.V.) at various doses (dose response)        over different time period's post MCAo.    -   A pre-determined concentration is infused over a pre-selected        time period beginning at various intervals post MCAo.    -   Vehicle-treated controls receive an infusion of normally 0.9        ml/hr.        A positive control compound is run at the same time.        Neurological Tests        Prior to surgery, 2 hours following the onset of ischaemia and        24 hours after ischaemia a battery of neurological tests are        performed.    -   The postural reflex test, which is designed to examine upper        body posture, when the rat is suspended by the tail above a flat        surface. A normal rat will extend the entire body and both        forelimbs towards the surface. Rats with an infarction will        consistently flex the contralateral limb and show signs of body        rotation.    -   The rats response to a gentle lateral push with a finger behind        the shoulders. A normal rat would resist such a push, whereas a        rat with an infarction will not.    -   The elicited forelimb placing in response to visual and tactile        stimuli. The animal is held by the body so that the lateral or        dorsal forepaw surface is placed against a bench. This test is        repeated but on this occasion obstructing the view of the rat.

Upon completion of each experiment, all animals are deeply anaesthetizedwith isoflurane (5%), euthanized by decapitation, and the brainsremoved, the extent and location of the ischaemic damage is verifiedhistologically by means of tetrazolium chloride.

Example 217

This Example illustrates the anti-inflammatory activity of the compoundsof this invention using a model of 2,4-dinitrobenzenesulfonic acid(DNBS) induced distal colitis (a model of inflammatory bowel disease).

1. Test Substance and Dosing Pattern.

A compound of this invention is dissolved in vehicle of 2% Tween 80 indistilled water for oral administration at a dose of 50 mg/kg ordissolved in vehicle of 2% Tween 80 and 0.9% NaCl for intraperitonealinjection at 30 mg/kg. The dose was given once daily for 7 consecutivedays. Dosing volume was 10 ml/kg. DNBS was challenged 2 hours afterdosing on the second day.

2. Animals

In these studies, male Wistar, Long Evans rats provided by animalbreeding center of MDS Panlabs Taiwan, Ltd. and Balb/cByJ derived malemice (weighing 20=2 gms), provided by National Laboratory AnimalsBreeding Research center (NALBRC, Taiwan), were used. Space allocationof 6 animals was 45×23×15 cm. Animals were housed in APEC® cages(Allentown Caging, Allentown, N.J. 08501, USA) in a positive pressureisolator (NuAire®, Mode: Nu-605, airflow velocity 50=5 ft/min, HEPAFilter) and maintained in a controlled temperature (22° C.-24° C.) andhumidity (60%-80%) environment with 12 hours light dark cycles for atleast one week in MDS Panlabs Taiwan laboratory prior to being used.Free access to standard lab chow for rats (Fwusow Industry Co., Limited,Taiwan) and tap water was granted. All aspects of this work includinghousing, experimentation and disposal of animals were performed ingeneral accordance with the International Guiding Principles forBiomedical Research Involving Animals (CIOMS Publication No. ISBN 9290360194, 1985).

3. Chemicals

DNBS is obtained from TCI, Tokyo, Japan, ethanol is from Merck, Germanyand Sulfasalazine is purchased from Sigma, USA.

4. Equipment

Electriconic scale (Tanita, model 1140, Japan), Electriconic scale(Sartorius, R160P, Germany), Glass syringe (2 ml, Mitsuba, Japan), Ratoral needle, Hypodermic needle (25G×1″ TOP Corporation, Japan),Stainless Scissors (Klappenclear, Germany), Stainless Forceps(Klappenclear, Germany).

5. Method

Groups of 3 Wistar derived male rats weighing 180±20 gms are used.Distal colitis is induced by intra-colonic instillation of DNBS(2,4-dinitrobenzene sulfonic acid, 30 mg in 0.5 ml ethanol 30%) afterwhich, 2 ml of air is gently injected through the cannula to ensure thatthe solution remains in the colon. Test substance is administered orally(PO) at a dose of 50 mg/kg or intraperitoneally (IP) at 30 mg/kg oncedaily for 7 consecutive days. DNBS is instillated into the distal colonof each animal 2 hours after dosing on the second day. The control groupis similarly treated with vehicle alone and sulfasalazine (300 mg/kg,PO) is used as reference agent. Animals are fasted 24 hours before DNBSchallenge and 24 hours after the final treatment when they aresacrificed and each colon was removed and weighed. During theexperiments, presence of diarrhea is recorded daily. When the abdominalcavity is opened before removal of the colon, adhesions between thecolon and other organs are noted. After weighing the colon, the extentof colonic ulceration is observed and noted as well. Colon-to-bodyweight ratio is then calculated for each animal according to theformula: Colon (g)/BW×100%. The “Net” increase in ratio ofVehicle-control+DNBS group relative to Vehicle-control group is used asa base value for comparison with test substance treated groups andexpressed as % decrease in inflammation. A 30 percent or more (30%)decrease in “Net” colon-to-body weight ratio for each test substancetreated group relative to the “Net” vehicle+DNBS treated group isconsidered significant.

The results from this study indicated that the test compound at a doseof 50 mg/kg×7 oral administration showed significant anti-inflammatoryactivity—46% inhibition relative to the vehicle control group. However,another treatment by intraperitoneal injection at a dose of 30 mg/kgcaused mortality in 3 out of 3 test animals on the 6^(th) day.Concurrently tested sulfasalazine (30 mg/kg×7, oral administration)showed 37% inhibition of the inflammation.

Example 218

This Example illustrates the anti-inflammatory activity of the compoundsof this invention using a model of carrageenan induced paw edema (amodel of inflammation, carrageenan).

1. Test Substance and Dosing Pattern.

A compound of this invention is dissolved in vehicle of 2% Tween 80/0.9%NaCl and administered intraperitoneally at a dose of 30 mg/kg 30 minutesbefore carrageenan (1% 0.1 ml/paw) challenge. Dosing volume is 10 ml/kg.

2. Animals

Animals are conditioned in accordance with the procedures set forth inExample 271.

3. Chemicals

Carrageenan is obtained from TCI, Japan; Pyrogen free saline is fromAstar, Taiwan; and Aspirin is purchased from ICN BioMedicals, USA.

4. Equipment

Glass syringe (1 ml and 2 ml Mitsuba, Japan), Hypodermic needle 24G×1″(Top Corporation, Japan), Plethysmometer #7150 (UGO Basile, Italy), andWater cell 25 mm Diameter, #7157 (UGO Basile, Italy).

5. Method

Test substance (Example) is administered IP (30 mg/kg) to groups of 3Long Evans derived male overnight fasted rats weighing 150±20 gms 30minutes before right hind paw injection of carrageenan (0.1 ml of 1%suspension intraplantar). Hind paw edema, as a measure of inflammation,is recorded 3 hours after carrageenan administration using aplethysmometer (Ugo Basile Cat. # 7150) with water cell (25 mm diameter,Cat. # 7157). Reduction of hind paw edema by 30 percent or more (≧30%)indicated significant acute anti-inflammatory activity.

The results from this study indicated that the compound of thisinvention at a dose of 30 mg/kg IP, showed significant anti-inflammatoryactivity—61% inhibition relative to the vehicle control group.Concurrently tested aspirin (150 mg/kg, PO) showed 38% inhibition ofinflammation.

Example 219

This Example illustrates the anti-inflammatory activity of the compoundsof this invention using a model of Balb/c mice subjected to monoclonalantibody (mAb) type II collagen induced arthritis.

1. Test Substance and Dosing Pattern.

A compound of this invention is dissolved in vehicle of 2% Tween 80/0.9%NaCl, at doses of 50 or 30 and administered orally (50 mg/kg) orintraperitoneally at 30 mg/kg once daily for 3 consecutive days aftermonoclonal antibody of collagen was injected. Dosing volume is 20 ml/kg.

2. Animals

Animals are conditioned in accordance with the procedures set forth inExample 271.

3. Chemicals

Lipopolysaccharide is obtained from Sigma, USA; Indomethacin is fromSigma, USA; Arthrogen-CIA™ Monoclonal Antibodies D8, F10, DI-2G and A2are obtained from IBL, Japan; Phosphated-Buffer Saline is purchased fromSigma, USA; and Tween 80 is from Wako, Japan.

4. Equipment

Plethysmometer (Ugo Basile, Italy) and Water Cell (Ugo Basile, Italy).

5. Method

Groups of 5 Balb/cByJ mice strain, 6-8 weeks of age, are used for theinduction of arthritis by monoclonal antibodies (mAbs) responding totype II collagen, plus lipopolysaccharide (LPS). The animals areadministered intravenously with a combination of 4 different mAbs (D8,F10, DI-2G and A2) in total of 4 mg/mouse at day 0, and followed byintravenous 25 μg of LPS 72 hours later (day 3). From day 3, one hourafter LPS administration, ML-659 at 50 mg/kg (PO) or 30 mg/kg (IP) andvehicle (2% Tween 80/0.9% NaCl, PO) as well as the positive controlindomethacin, 3 mg/kg (PO) are administrated once daily for 3consecutive days. A plethysmometer (Ugo Basile Cat # 7150) with watercell (12 mm diameter) is used for the measurement of increase in volumeof the two hind paws at day 0, 5, 7, 10, 14, and 17. The percentinhibition of increase in volume is calculated by the following formula:Inhibition (%): [1−(Tn−To)/(Cn−Co)]×100Where:Co (Cn): volume of day 0 (day n) in vehicle controlTo (Tn): volume of day 0 (day n) in test compound-treated groupThe reduction of both of two hind paws edema by more than 30% isconsidered significant.

The results from this study indicated that the compound of thisinvention at doses of 50 mg/kg (PO) and 30 mg/kg (IP), administered oncedaily for 3 consecutive days, significantly reduced inflammation.Significant reduction in inflammation is achieved relative to vehicletreated group of both hind paws edema at 30 mg/kg (IP) on days 5, 7, 10,14 and 17 with reduction in inflammation of 100%, 72%, 71%, 86% and 85%,respectively. At a dose of 50 mg/kg (PO), on day 14, 36% reduction andon day 17, 28% reduction in inflammation are observed. Concurrentlytested indomethacin (3 mg/kg×3, PO) provided an effect of 63%, 70%, 80%,88% and 85% at days 5, 7, 10, 14 and 17 respectively, relative to thevehicle treated group.

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

1. A compound of formula II or a pharmaceutically acceptable saltthereof:

wherein: R is hydrogen, or C₁₋₆ alkyl; R₁ and R₃ taken together with thecarbon atoms to which they are attached form a cyclopentane,cyclohexane, cycloheptane or cyclooctane; R₂ and R₄ are the same ordifferent and are each independently selected from: hydrogen, C₁₋₆ alkylor fluoroalkyl of the formula C_(n)H_(x)F_(y), wherein n is an integerfrom 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9and sum of x and y is 2n+1; R₅ is phenyl, which is optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁₋₄ alkyl, fluoroalkyl of the formulaC_(n)H_(x)F_(y) and fluoroalkoxy OC_(n)H_(x)F_(y) wherein n is aninteger from 1 to 4, x is an integer from 0 to 8, y is an integer from 1to 9 and sum of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, aminoC₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl, C₁₋₄ dialkylamino C₁₋₄ alkyl,—CN, —CO₂H, —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)—, wherein (CH₂) is optionally substituted withone or more groups selected independently from: hydroxy, C₁₋₆ alkoxy,arylaminocarbonyloxy, C₃₋₈ cycloalkyl, and fluoroalkyl of the formulaC_(n)H_(x)F_(y), wherein n is an integer from 1 to 4, x is an integerfrom 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1,wherein said alkoxy or fluoroalkyl is optionally substituted with asubstituent selected from the group consisting of: hydroxy, —SH, C₁₋₄alkoxy, C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,C₁₋₄ dialkylamino, —CN, —CO₂H, —CO₂C₁₋₄ alkyl and aryl; Z is NR₆,wherein R₆ is selected from: hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl orfluoroalkyl of the formula C_(n)H_(x)F_(y), wherein n is an integer from1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sumof x and y is 2n+1, wherein said alkoxy or alkyl or fluoroalkyl isoptionally substituted with at least one substituent selected from thegroup consisting of: hydroxy, —SH, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, C₁₋₄acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, —CN, —CO₂H,—CO₂C₁₋₄ alkyl and aryl; and a is 0 and b is an integer from 1 to
 4. 2.The compound as set forth in claim 1 wherein X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)— and wherein Z is NR₆ and wherein R₆ is hydrogenor methyl, and a is 0 and b is
 1. 3. The compound as set forth in claim2 wherein R₁ and R₃ taken together with the carbon atoms to which theyare attached form a cyclohexane, and R, R₂ and R₄ are hydrogen.
 4. Thecompound as set forth in claim 3 which is selected from the groupconsisting of:(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-benzylamine,(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(3-fluorobenzyl)amine,(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(4-fluorobenzyl)amine,and(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(3,4-difluorobenzyl)amine.5. The compound as set forth in claim 1 wherein X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)—and wherein Z is NR₆ and wherein R₆, is hydrogen,a is 0 and b is
 2. 6. A pharmaceutical composition comprising a compoundor a pharmaceutically acceptable salt thereof in combination with atleast one pharmaceutically acceptable carrier, wherein said compound isof the formula (II):

wherein: R is hydrogen, or C₁₋₆ alkyl; R₁ and R₃ taken together with thecarbon atoms to which they are attached form a cyclopentane,cyclohexane, cycloheptane or cyclooctane; R₂ and R₄ are the same ordifferent and are each independently selected from: hydrogen, C₁₋₆ alkylor fluoroalkyl of the formula C_(n)H_(x)F_(y), wherein n is an integerfrom 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9and sum of x and y is 2n+1; R₅ is phenyl, which is optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁₋₄ alkyl, fluoroalkyl of the formulaC_(n)H_(x)F_(y) and fluoroalkoxy OC_(n)H_(x)F_(y) wherein n is aninteger from 1 to 4, x is an integer from 0 to 8, y is an integer from 1to 9 and sum of x and y is 2n+1, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, hydroxy,C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, aminoC₁₋₄ alkyl, C₁₋₄ alkylamino C₁₋₄ alkyl, C₁₋₄ dialkylamino C₁₋₄ alkyl,—CN, —CO₂H, —CO₂C₁₋₄ alkyl, phenyl, phenoxy and benzyloxy; X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)—, wherein (CH₂) is optionally substituted withone or more groups selected independently from: hydroxy, C₁₋₆ alkoxy,arylaminocarbonyloxy, C₃₋₈ cycloalkyl, and fluoroalkyl of the formulaC_(n)H_(x)F_(y), wherein n is an integer from 1 to 4, x is an integerfrom 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1,wherein said alkoxy or fluoroalkyl is optionally substituted with asubstituent selected from the group consisting of: hydroxy, —SH, C₁₋₄alkoxy, C₁₋₄ thioalkyl, C₁₋₄ acyloxy, nitro, amino, C₁₋₄ alkylamino,C₁₋₄ dialkylamino, —CN, —CO₂H, —CO₂C₁₋₄ alkyl and aryl; Z is NR₆,wherein R₆ is selected from: hydrogen, C₁₋₆ alkoxy, C₁₋₆ alkyl orfluoroalkyl of the formula C_(n)H_(x)F_(y), wherein n is an integer from1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sumof x and y is 2n+1, wherein said alkoxy or alkyl or fluoroalkyl isoptionally substituted with at least one substituent selected from thegroup consisting of: hydroxy, —SH, C₁₋₄ alkoxy, C₁₋₄ thioalkyl, C₁₋₄acyloxy, nitro, amino, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, —CN, —CO₂H,—CO₂C₁₋₄ alkyl and aryl; and a is 0 and b is an integer from 1 to
 4. 7.The composition as set forth in claim 6 wherein X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)— and wherein Z is NR₆ and wherein R₆ is hydrogenor methyl, and a is 0 and b is
 1. 8. The composition as set forth inclaim 7 wherein R₁ and R₃ taken together with the carbon atoms to whichthey are attached form a cyclohexane, and R, R₂ and R₄ are hydrogen. 9.The composition as set forth in claim 8 wherein the compound is selectedfrom the group consisting of:(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-benzylamine,(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(3-fluorobenzyl)amine,(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(4-fluorobenzyl)amine,and(cis-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-(3,4-difluorobenzyl)amine.10. The composition as set forth in claim 6 wherein X—Y is—(CH₂)_(a)—Z—(CH₂)_(b)— and wherein Z is NR₆ and wherein R₆ is hydrogen,a is 0 and b is 2.